Chapter 66. Treatment of Chronic Pain Syndromes

Chapter 66. Treatment of Chronic Pain Syndromes

TREATMENT OF CHRONIC PAIN SYNDROMES: INTRODUCTION

Pain is the most common symptom reported in both the general population and the general medical setting (Kroenke

2003b; Sternbach 1986; Verhaak et al. 1998). Pain complaints account for more than 40% of all symptom-related

outpatient visits, or over 100 million ambulatory encounters in the United States alone each year (Schappert 1992). Pain

costs the United States more than $100 billion each year in health care and lost productivity (Stewart et al. 2003). Pain

medications are the second most commonly prescribed class of drugs (after cardiac-renal drugs), accounting for 12% of

all medications prescribed during ambulatory office visits in the United States (Turk 2002). Yet nonopioid analgesics fail to

provide adequate relief in many patients (Curatolo and Bogduk 2001), and physicians’ concerns about regulatory

restrictions as well as risks of tolerance or addiction constrain the prescribing of opioid analgesics for noncancer pain

(Joranson et al. 2002). Moreover, opioids themselves may produce only moderate reductions in chronic pain (Furlan et al.

2006; Martell et al. 2007; Turk 2002) and may fail to improve (or may even worsen) psychological outcomes (e.g.,

depression) or functional status even when they do alleviate the pain (Moulin et al. 1996). At the same time, clinicians are

being pressured to respond to pain as the “fifth vital sign” (Joint Commission on Accreditation of Healthcare Organizations

2000). In House Resolution 1863, the National Pain Care Policy Act of 2003, Congress declared this the “Decade of Pain

Control and Research.” Indeed, persistent pain is a major international health problem (Gureje et al. 1998), prompting the

World Health Organization to endorse a global campaign against pain (Breivik 2002). Persistent pain may lead to

excessive surgery or other expensive or invasive procedures and is the leading reason for use of complementary and

alternative medicine (CAM) (Astin 1998). Pain is also among the most common reasons for temporary as well as

permanent work disability (B. H. Smith et al. 2001). Many pain treatment recommendations are based principally on

expert consensus rather than on clinical trial results (Bair et al. 2005) and have yet to influence primary care practice

(Chodosh et al. 2001).

PSYCHIATRIC COMORBIDITY

Pain is even more prevalent in patients with psychiatric comorbidity, particularly mood disorders. The overlap between

pain and depression ranges from 30% to 60% (Ang et al. 2006; Bair et al. 2003; Magni et al. 1993). Pain is a strong

predictor of both the onset and persistence of depression (Ohayon and Schatzberg 2003), and depression is likewise a

powerful predictor of pain, particularly persistent pain (Bair et al. 2003; Gureje et al. 1998). Concurrent pain and

depression have a much greater impact than either disorder alone on multiple domains of functional status as well as

health care utilization (Bair et al. 2003). Comorbid depression worsens disability and decreases active coping in patients

suffering from pain (Arnow et al. 2006; Demyttenaere et al. 2006). Comorbidity decreases the likelihood of a favorable

response of either condition to treatment and also diminishes patient satisfaction with treatment (Bair et al. 2004; Karp et

1. 2005; Kroenke et al. 2008; Mavandadi et al. 2007; Thielke et al. 2007). Thus, reliable methods for assessing the

presence and severity of pain in patients with depression (particularly those not responding to initial treatment) and

strategies for effectively and efficiently integrating evidence-based depression care into the management of patients with

chronic pain are sorely needed (Kroenke 2003a).

Although not as extensively studied, the comorbidity of pain with anxiety appears to be nearly as strong as its comorbidity

with depression (Kroenke 2003b; Kroenke and Price 1993; Kroenke et al. 1994, 1997; McWilliams et al. 2003). Indeed, a

global study conducted by the World Health Organization in 17 countries involving more than 85,000 community-dwelling

adults showed that pain is associated with mood and anxiety disorders, but not with alcohol abuse or dependence (Gureje

et al. 2008). The prevalence of specific mood and anxiety disorders was lowest among persons with no pain, intermediate

among those with one pain site, and highest among those with multiple pain sites. Relative to persons not reporting pain,

the age–sex adjusted odds ratios were 1.8 (95% confidence interval [CI] = 1.7–2.0) for mood disorders and 1.9 (95% CI

= 1.8–2.1) for anxiety disorders for persons with single-site pain, and 3.7 (95% CI = 3.3–4.1) for mood disorders and 3.6

(95% CI = 3.3–4.0) for anxiety disorders among those with multisite pain.

DEFINITION AND CLASSIFICATION OF PAIN

The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional

experience associated with actual or potential tissue damage, or described in terms of such damage.” Although there are

more complex approaches to classifying pain, a pragmatic and frequently used system broadly classifies pain as either

nociceptive or neuropathic (Basbaum et al. 2005). Nociceptive pain includes most cases of acute pain in which a strong,

noxious stimulus impacts the skin or deep tissue. Acute pain resolves after the noxious stimulus has been removed, but

inflammatory and other mechanisms may lead to persistence of nociceptive pain for weeks, months, or years (i.e., chronic

pain). Many pain conditions, including arthritis and other musculoskeletal disorders, migraine and tension headache, and

chronic widespread pain conditions such as fibromyalgia, would be classified under the broad rubric of nociceptive pain.

A second type of chronic pain, neuropathic pain, arises from injury to the peripheral or central nervous system. Examples

include postherpetic neuralgia, painful diabetic neuropathy, phantom limb pain, and sciatica. Neuropathic pain is oftenPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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characterized as burning, paroxysmal, stabbing, buzzing, or electric shock–like. Some conditions, such as low back pain,

may include both nociceptive components (arising from the muscles or contiguous tissues) and neuropathic components

(radicular pain or sciatica).

Persons with chronic pain often suffer from spontaneous ongoing pain. Also, stimuli that are normally not painful

(movement, light touch) become painful, a phenomenon known as allodynia. Examples include pain produced by touching

sunburned skin or moving an arthritic joint. Hyperalgesia is exacerbated pain produced by a stimulus that is expected to

be only mildly painful (e.g., slapping sunburned skin). These phenomena may be related to central sensitization, which has

been proposed as a common mechanism underlying unexplained pain syndromes such as fibromyalgia.

Sometimes, the broader category of nociceptive pain is subclassified into somatic pain (triggered in the skin, muscles,

joints, or fascia) and visceral pain (heart, lungs, gastrointestinal or genitourinary system, or other deeper organs). The

latter is diffuse and poorly localized, reflecting differences in innervation between somatic and visceral tissue.

Somatosensory fibers are precisely located in the spinal cord and brain, whereas afferent viscerosensory fibers overlap

each other and converge at several levels within the nervous system. Although some of the principles of pain management

are relevant to visceral pain, in this chapter we concentrate on the management of chronic pain due to nociceptive pain of

the somatic variety and neuropathic pain conditions. Together, these account for the majority of chronic pain conditions

seen in clinical practice. Moreover, visceral pain is more commonly a harbinger of a serious underlying disorder with

specific treatments targeting the disease itself rather than mere analgesia. In contrast, pain itself becomes the primary

“disease” or target of therapy in a large proportion of chronic somatic and neuropathic pain disorders.

TREATMENT OF PAIN

Overview

The focus of this chapter is twofold. First, we discuss major classes of medications as they relate to pain management.

Because a number of drugs are effective across multiple types of pain disorders, it is useful to consider them in a

cross-cutting as well as a disease-specific fashion. Nonpharmacological treatments are also reviewed. In the following

main section (“Selected Pain Disorders”), we briefly address several specific categories of disorders chosen because they

1) account for the most common types of chronic pain, 2) are conditions for which pain management is the principal focus,

and 3) have been studied in numerous clinical trials. In short, prevalence, pain management as a priority rather than

disease modification, and evidence-based therapy are the three selection criteria for the discussion of specific disorders.

Even within these two broad foci (disorders and treatments), there will perforce be some intermingling. For example,

certain drug classes have been heavily studied within certain pain disorders, and conversely, certain pain disorders have

been a common target of several classes of medications or other treatments.

The prototypical diseases discussed are musculoskeletal disorders (principally fibromyalgia, low back pain, and

osteoarthritis) and neuropathic pain. Musculoskeletal disorders account for more than two-thirds of pain-related

outpatient visits, and neuropathic pain not only is common but also is a popular target for clinical trials in pain

management and therefore a common reason for seeking U.S. Food and Drug Administration (FDA) approval of pain as a

drug indication. Although pharmacotherapy receives the greatest attention in this chapter, we briefly review

nonpharmacological treatments due to their important role in the management of chronic pain. Acute pain (e.g., injuries,

postoperative pain), cancer pain, headache, and visceral pain are not addressed. Although a moderate amount of the

information presented in this chapter is relevant to the treatment of pain in these and other conditions (especially the

discussion of specific analgesics), a detailed discussion of these specialized topics is beyond the scope of this chapter.

Strength of Evidence

The majority of the information in this chapter was derived from meta-analyses and systematic reviews published since

2005. Individual randomized, controlled trials (RCTs) are not presented unless they reported on a promising treatment for

which multiple trials had not yet been performed. Certainly, evidence is strongest for those treatments that have shown

efficacy in multiple trials rather than a single RCT, particularly because individual trials sometimes yield contradictory

findings. Uncontrolled or open-label studies provide still weaker evidence and are cited only in a few instances.

In meta-analyses and systematic reviews, the magnitude of a treatment’s effect on particular domains such as pain and

physical function is often reported as an effect size. The effect size is a standard way to determine the degree of

improvement (or change) related to a particular therapy compared with a placebo or other type of control group. The

effect size is calculated as the mean change in the treatment group minus the mean change in the control group, divided

by the pooled standard deviation. By convention, an effect size of less than 0.2 is considered trivial; 0.2–0.5, small;

0.5–0.8, moderate; 0.8–1.2, important; and 1.2 or greater, very important (Cohen 1998).

Effect size can be useful when comparing continuous variables such as mean differences (e.g., in pain scores). When

comparing response rates on a categorical variable (e.g., “improved” or ” 50% reduction in pain”), the number needed to

treat (NNT) is another common metric. The NNT is calculated as the reciprocal of the absolute difference between

treatment groups. For example, if a clinical trial demonstrates that 60% of subjects improve while taking a new analgesic

versus 35% of subjects receiving a placebo, that is an absolute difference of 25%. The NNT is the reciprocal of that:

1/0.25 = 4. This means that for every four patients who receive the analgesic, one additional patient would achieve a

therapeutic response over and above placebo (i.e., the other three patients may have done just as well taking the

placebo). Actually, an NNT of 5 typically represents a reasonably good analgesic.

When studying the same pain condition, the NNT may also be useful in comparing different drugs. For example, in onePrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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study of acute pain after certain operative procedures, 10 mg of morphine, 30 mg of ketorolac, and 100 mg of meperidine

(all administered by intramuscular injection) and 1,000 mg of acetaminophen (administered orally) all had NNTs between

3 and 4; furthermore, their 95% confidence intervals overlapped, implying no significant difference in the analgesic

efficacy between intramuscular opioids, intramuscular nonsteroidal anti-inflammatory drugs (NSAIDs), and oral

acetaminophen (Barden et al. 2004). However, analgesic effect may depend on the type of pain condition being treated or

clinical context as well. For example, one study found that the NNT for acetaminophen after dental extraction was 3.8,

compared with 1.9 after orthopedic surgery (Barden et al. 2004). Also, small sample sizes may affect the precision of NNT

estimates; some feel that NNT calculations based on trial data involving fewer than 500 subjects should be interpreted

cautiously. Second, it is more problematic to compare the NNTs of different drugs estimated from separate studies than

when NNTs are estimated for different drugs tested in the same clinical trial. Third, NNTs derived from studying analgesics

in acute pain conditions may not be readily generalizable to their efficacy in the treatment of chronic pain.

Pharmacotherapy

Nonopioid Analgesics

The anti-inflammatory properties of the extract of willow bark have been known for centuries. Salicylic acid was

discovered as the extract’s active ingredient in the nineteenth century and was subsequently acetylated to improve its

gastrointestinal tolerability; acetylsalicylic acid became the prototypical analgesic aspirin. Aspirin and other related

compounds constitute a class of drugs known as NSAIDs. All NSAIDs have three desirable pharmacological

effects—anti-inflammatory, analgesic, and antipyretic. NSAIDs and acetaminophen are among the most commonly

prescribed medications for acute and chronic pain and can also be obtained without a prescription.

Acetaminophen has analgesic and antipyretic effects similar to those of the NSAIDs but lacks a specific anti-inflammatory

effect. Despite its widespread use, the analgesic mechanism of acetaminophen is poorly understood. Acetaminophen is a

slightly weaker analgesic than NSAIDs (<10 point difference on a 100-point visual analog pain scale) (Lee et al. 2004;

Towheed et al. 2006; Wegman et al. 2004) but is a reasonable first-line option because of its more favorable safety profile

and low cost. However, acetaminophen is associated with asymptomatic elevations of aminotransferase levels at dosages

of 4 g/day even in healthy adults, although the clinical significance of these findings is uncertain (Watkins et al. 2006).

NSAIDs block the enzymatic activity of cyclo-oxygenase (COX), which uses arachidonic acid to generate prostanoids.

Prostanoids influence immune, cardiovascular, gastrointestinal, renovascular, pulmonary, central nervous system, and

reproductive function. Although gastrointestinal adverse effects have traditionally been considered the most common and

worrisome complication, cardiovascular risk has gained increasing attention (Antman et al. 2007). Aspirin was the first

and at one time the most commonly used NSAID.

There are two major COX isoenzymes: COX-1 is expressed constantly in most tissues, whereas COX-2 is induced by

inflammation. NSAIDs vary in their chemical structure and relative ability to block the COX-1 versus the COX-2

isoenzymes. Several prostaglandins are both hyperalgesic and gastroprotective. Thus, nonselective COX inhibition with

NSAIDs like aspirin, ibuprofen, indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes, provides

effective pain relief for inflammatory conditions but carries a risk for erosive gastritis and gastrointestinal bleeding.

Selective COX-2 inhibitors (valdecoxib, rofecoxib, celecoxib) have less gastrointestinal toxicity because of the relative

paucity of COX-2 expression in the gastrointestinal tract relative to inflammatory tissue. However, data from

meta-analyses and registries have shown an increased risk of cardiovascular events and mortality from COX-2 use,

particularly in patients with known cardiovascular disease who receive prolonged treatment. Rofecoxib (Vioxx) has been

withdrawn from the market, and all COX-2 inhibitors should be used cautiously, if at all, in patients with cardiovascular

disease or risk factors for cardiovascular disease. All NSAIDs, including nonselective COX inhibitors and COX-2 agents,

appear equally effective in the treatment of pain disorders (Chou et al. 2006). The NSAID that appears to be the safest in

terms of cardiovascular risk is naproxen.

Opioid Analgesics

The analgesic effects of opium have been known to mankind for more than 5,000 years. However, their inherent risk of abuse soon

became evident. Ever since, society has attempted to find a balance between licit and illicit use, therapeutic versus adverse

effects, and medical needs and legal issues. Despite all the legal, administrative, and social interference, no other class of drugs

has remained in use for as long as opioids. (Schug 2005)

Opioids have a leading place in the treatment of acute pain and advanced cancer pain of moderate to severe intensity,

because in both instances treatment is expected to be of short to medium duration. In contrast, opioid treatment for

chronic noncancer pain is frequently delayed until first- or second-line treatments have failed because of less clarity about

the benefits of chronic use and greater concerns about addiction, long-term effects (e.g., immunological, reproductive),

opioid-induced hyperalgesia, and regulatory difficulties.

The Controlled Substances Act of 1970 divided substances to be regulated into five schedules, as determined by the U.S.

Drug Enforcement Administration. These schedules govern the legal distribution and use of most substances with a

significant abuse liability. Schedule I drugs have the highest abuse potential; they are available for research only and have

no approved medical uses. Schedule II–IV substances have decreasing abuse liabilities (II is the highest) and approved

medical uses. Physicians are licensed to prescribe these compounds, and pharmacies can dispense them, although

pharmacies do not stock all of these substances. Schedule II compounds have more stringent record-keeping and storage

requirements than do Schedule III and Schedule IV substances. Schedule V substances have a recognized abuse liabilityPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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(and approved medical uses) but are generally not as highly regulated vis-à-vis record keeping. Many of these substances

are used in common over-the-counter medicines. Including compounds on this schedule facilitates state and local

regulations deemed appropriate in some jurisdictions (e.g., an individual state may impose restrictions on some substance

considered to have an unexpectedly high abuse liability).

Propoxyphene and tramadol

Two drugs are “on the border” of what are traditionally considered opioids. Propoxyphene is a lower-scheduled drug than

other opioids, and tramadol has been an unscheduled drug. Still, the efficacy and toxicity of both drugs are related, at

least in part, to opioid effects, and thus they are discussed within this category.

Propoxyphene (Darvon) had, until recently, been one of the most widely prescribed analgesics for mild to moderate pain.

It is often used in combination with acetaminophen (as Darvocet) or aspirin (Darvon Compound). Experts increasingly

advise against its use for several reasons (Pasero et al. 1999). First, its therapeutic–toxicity ratio is not particularly

favorable. Propoxyphene is only one-half to one-third as potent as codeine. Its recommended dose of 100 mg is equal in

analgesic effect to 60 mg of codeine, which is known to be equal to 600 mg (less than two 325-mg tablets) of aspirin. Yet

at equianalgesic doses, propoxyphene has the same incidence of minor side effects as codeine. More importantly,

propoxyphene and its active metabolite, norpropoxyphene, can accumulate in the body and produce severe toxicity with

repeated doses. Respiratory depression, sedation, and cognitive impairment can occur with excessive accumulation or

when propoxyphene is used in combination with alcohol or sedating medications, and elderly patients may be particularly

sensitive due to poorer renal clearance.

Tramadol (Ultram) is unique in that it has both opioid and nonopioid effects. Although its mode of action is not completely

understood, it exerts an analgesic effect through binding to the opioid receptor as an agonist (opioid effect) and weakly

inhibiting the reuptake of serotonin and norepinephrine (nonopioid effect), similar to the effect of tricyclic antidepressants

(TCAs). Tramadol is available in both short- and long-acting formulations. The starting dosage for the short-acting

formulation is 50 mg once or twice daily, with gradual titration to a maximum of 400 mg/day. Dosage reduction is

necessary in those with renal or hepatic disease. The risk of respiratory depression and, presumably, addiction is lower

than with other opiates. Because tramadol is an unscheduled drug, clinicians may not be aware of its opioid effect.

However, it still should be used with some caution in persons recovering from substance use disorders. Dose reduction is

recommended in older adult patients (>75 years) and in those with renal impairment (creatinine clearance <30

mL/minute) or cirrhosis of the liver. Multiple trials have demonstrated the efficacy of tramadol in pain disorders,

particularly osteoarthritis, fibromyalgia, and neuropathic pain.

Hollingshead et al. (2006) conducted a systematic review of six trials evaluating tramadol in neuropathic pain. All four

trials comparing tramadol with placebo showed benefit with tramadol: the NNT with tramadol versus placebo to reach at

least 50% pain relief was 3.8. Single trials comparing tramadol with clomipramine or morphine were inconclusive.

In summary, the clinical trial evidence across a number of pain disorders is much stronger for tramadol, which has led to

its recommendation as at least a second-line treatment for conditions such as osteoarthritis, fibromyalgia, and

neuropathic pain. In contrast, the benefits of propoxyphene have not been clearly shown to exceed its potential risks.

Efficacy of opioids

Furlan et al. (2006) conducted a meta-analysis of opioid use for chronic noncancer pain. Included were 41 trials involving

6,019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis, or back pain); 12%,

neuropathic pain (postherpetic neuralgia, diabetic neuropathy, or phantom limb pain); 7%, fibromyalgia; and 1%, mixed

pain. For certain analyses, the authors classified opioids as weak (propoxyphene, tramadol, codeine) and strong (all other

opioids). Tramadol was the agent studied in 17 trials (3,433 patients), propoxyphene or dextropropoxyphene in 3 trials

(1,074 patients), codeine in 7 trials (444 patients), oxycodone in 6 trials (517 patients), and morphine in 8 trials (551

patients). Average duration of treatment was 5 weeks (range, 1–16 weeks). On average, 33% of patients in the opioid

groups dropped out (15% because of inadequate pain relief and 21% because of side effects; some patients reported both

reasons), as did 38% in the placebo groups (30% because of inadequate pain relief and 10% because of side effects).

Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or

neuropathic pain. The only opioid studied for fibromyalgia was tramadol (2 trials, 228 patients), where it proved effective.

The effect size for opioids compared with placebo was moderate for pain (–0.60) and small for functional outcomes

(–0.31). Only 8 trials compared opioids with other analgesics; in these trials, opioids did not differ significantly from

nonopioids in terms of pain relief (effect size, –0.05) and were significantly worse than nonopioids in terms of functional

outcomes, although only slightly so (effect size, 0.16). The authors concluded that the strong opioids (oxycodone,

morphine) were significantly more effective than other drugs (effect size, –0.34), but this was based on only 2 trials, one

of which was an open-label study (Furlan et al. 2006).

A systematic review reported on 11 studies (2,877 patients) that assessed quality of life in patients with chronic

nonmalignant pain receiving long-term opioid treatment (Devulder et al. 2005). Six studies were randomized trials and

five were observational studies. Of the 4 trials in which baseline values were reported, 3 showed an improvement in

quality of life. Similarly, it improved in 4 of the 5 observational studies. While this suggests potential quality-of-life

benefits, the authors concluded that further methodologically rigorous studies are needed to confirm these findings and to

elucidate the potential adverse effects of physical tolerance, withdrawal, and addiction on functional status.

Adverse effectsPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Moore and McQuay (2005) conducted a systematic review of 34 trials with 4,212 patients that provided information on

adverse events related to opioid use in treating noncancer pain. Most opioids used (accounting for 90% of patients) were

for treating moderate rather than severe pain. Dry mouth (affecting 25% of patients), nausea (21%), and constipation

(15%) were the most common adverse events. A substantial proportion of patients taking opioids (22%) withdrew

because of adverse events. Because most trials were short (<4 weeks) and did not use titrated doses, the implications for

long-term use in clinical practice are less certain. Eisenberg et al. (2006) also reported on adverse events in their

systematic review of opioids for neuropathic pain. Compared with placebo recipients, opioid recipients had higher rates of

nausea (33% vs. 9%), constipation (33% vs. 10%), drowsiness (29% vs. 12%), dizziness (21% vs. 6%), and vomiting

(15% vs. 3%). Among studies reporting causes of withdrawal, more patients receiving opioids withdrew because of

adverse effects (11% vs. 4%). Finally, in the review by Furlan et al. (2006), only three side effects occurred significantly

more frequently with opioids than with placebo: nausea, constipation, and somnolence. These rates were 14%, 9%, and

6% higher in opioid recipients, respectively.

A large population-based study from Denmark found that opioid usage was significantly associated with more severe pain,

poorer self-rated health, lower quality of life, less physical activity, lower employment, higher levels of health care

utilization, and more subjects living alone (Højsted and Sjøgren 2007). The cross-sectional nature of the study does not

prove causation, and it is certainly possible that the opioid users would have fared worse without opioid treatment.

However, it does raise questions of whether opioid treatment of chronic pain is achieving the key goals of pain relief,

improved functional status, and better quality of life.

Studies have indicated that endocrinological abnormalities such as hypogonadism and erectile dysfunction may be

associated with opioid therapy (Ballantyne and Mao 2003; Daniell 2002). In women, opioid use has been associated with

amenorrhea and decreased sex hormone levels (Daniell 2008). Two small trials evaluating opioid use in chronic pain

reported analyzable data regarding sexual activity, and both found that patients taking opioids had better self-reported

sexual function than those taking placebo (Furlan et al. 2006). Improvement of well-being secondary to better pain

control may account for this. Clearly, the incidence and clinical significance of opioid-related hypogonadism need to be

better defined.

A feared consequence of long-term opioid use is cognitive dysfunction. Studies have suggested that opioid treatment for

chronic pain may be associated with impaired neuropsychological performance regarding reaction times, psychomotor

speed, and working memory (Højsted and Sjøgren 2007). However, many other factors may be playing a role, including

pain itself, concomitant medications, and psychiatric comorbidity. A systematic review concluded that stable doses of

opioids do not impair driving performance (Fishbain et al. 2003).

Tolerance and addiction

The risks of prescription opioid addiction, abuse, and diversion among chronic pain patients are not well understood. In

part, this is due to inconsistent use of terminology and the difficulty of defining addiction and abuse in patients receiving

opioids for chronic pain (Heit 2003; Savage et al. 2003). The term dependence is particularly problematic because

confusion can occur between physical dependence, psychological dependence, and substance dependence (as defined in

DSM-IV-TR [American Psychiatric Association 2000]). Some experts believe that the term addiction should be reserved for

the specific condition defined as substance dependence in DSM-IV-TR. Misuse describes other problematic opioid use,

including DSM-IV-TR substance abuse and other nontherapeutic uses that do not meet DSM-IV-TR criteria. Diversion

includes selling, sharing, and trading of prescription opioids.

A systematic review of the literature on the risk of iatrogenic addiction in patients treated with opioids for acute and

subacute pain yielded 41 eligible articles (Wasan et al. 2006). However, there were no randomized trials or comparative

longitudinal studies, and the results of nine studies of low methodological quality yielded conflicting findings. The authors

concluded that it is not known whether the risk for iatrogenic addiction among patients treated for acute or subacute pain

is relatively high (>10%) or low (<0.1%).

In a 10-year follow-up study of patients treated with opioids for chronic pain, tolerance was not a problem in the majority

of patients (Jensen et al. 2006). In contrast, a retrospective study of 104 chronic pain patients younger than 50 years and

102 patients older than 60 years showed that younger patients and those with nociceptive pain (as compared with

neuropathic pain) had much higher escalation of opioid doses over a 15-month follow-up period (Buntin-Mushock et al.

2005). Another worrying finding of this study was that although the younger patients had a dosage increase of 640%

(from 49 to 365 mg/day of morphine equivalent) during the observation period, the pain visual analog scale scores did not

change at all. Although this does not mean that addiction is playing an important role, it does suggest that decisions about

dose escalation may need to vary depending on the type of pain, patient age, treatment response, and other factors.

Failure of pain to improve with moderate dosage increases in an individual patient may indicate that opioids are not the

optimal treatment rather than that continuing dose escalations are needed. Some experts have classified patients or pain

syndromes as opioid responsive versus opioid resistant (H. S. Smith 2005). Indeed, some patients may develop

opioid-induced hyperalgesia where the balance between anti-nociceptive and pro-nocioceptive systems is upregulated

after opioid exposure, leading to an enhanced vulnerability to pain (Angst and Clark 2006; Højsted and Sjøgren 2007).

Højsted and Sjøgren (2007) reviewed some important predictors of opioid use. The “rush” the patient experiences after

administration of an opioid is caused by a rapid and large increase in dopamine in the brain reward system. Important

factors for abuse liability associated with the drug include the speed of access and the concentration at the target sites.

On a scale of opioid attractiveness, sustained-release oxycodone had the highest rating and the fentanyl patch had the

lowest score; oral transmucosal fentanyl, methadone, and sustained-release morphine had intermediate scores. However,Print: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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research demonstrating higher abuse potential of one opioid versus another is limited. Risk factors for opioid abuse in

patients with chronic pain are young age, male gender, past alcohol or cocaine abuse, previous drug conviction, mental

health disorders, pain in multiple regions, and pain after motor vehicle accidents.

A randomized trial of 11,352 participants with chronic noncancer pain compared the abuse potential of tramadol, NSAIDs,

and hydrocodone (Adams et al. 2006). Abuse was defined by an algorithm including increasing doses without physician

approval, use for purposes other than the ones intended, inability to stop using the drug, and withdrawal. The percentage

of subjects who scored positive for abuse at least once during the 12-month follow-up period was 2.5% with NSAIDs,

2.7% with tramadol, and 4.9% with hydrocodone. When more than one algorithm criterion was required, abuse rates were

0.5% with NSAIDs, 0.7% with tramadol, and 1.2% with hydrocodone. Although the authors concluded that the prevalence

of abuse/dependence was significantly less with NSAIDs and tramadol than with hydrocodone, the rates are overall quite

low and the between-group differences are rather small.

General principles of opioid use

Useful suggestions for management of chronic opioid therapy have been published (Ballantyne 2006; Kahan et al. 2006;

Pasero et al. 1999). The use of very high doses of opioids is rarely helpful. Purely on the basis that the highest daily

dosage of opioids used in existing trials is 180 mg of morphine or its equivalent, opioid reduction or rotation should be

considered at this point. Because of incomplete cross-tolerance (i.e., patients may be tolerant to high doses of the first

opioid yet have a lower tolerance to the new opioid), the initial dosage of a new opioid should be equivalent to 50% or

less of the dosage of the original opioid. Equianalgesic doses of oral and transdermal opioids are summarized in Table

66–1. When trials of several opioids are ineffective in chronic pain, it is appropriate to consider weaning patients off the

drug and discontinuing its use. Weaning can usually be accomplished over 10 days, but the exact weaning schedule

depends on dose, drug, and duration of treatment. In cases of addiction, referral to an addiction specialist may be

preferable to drug discontinuation. Opioids are often best used as an adjunctive treatment rather than as the sole therapy

for chronic pain. Before starting opioid therapy, patients should understand that the goal of treatment is not the complete

elimination of pain but a 25%–50% reduction in its intensity and improvement in mood and functioning.

TABLE 66–1. Oral and transdermal opioid analgesic equivalence

Drug Dose (mg)

Duration (hours)a

Morphine 20–30 2–4

Codeine

200b

3–4

Hydrocodone

30c

4–6

Oxycodone 20 3–4

Hydromorphone 7.5 3–4

Meperidine

300b

2–4

Methadone

20d

4–8

Fentanyl (transdermal) 0.001/hour (1 g/hour)e 48–72

aDuration of analgesia is dose-dependent; the higher the dose, usually the longer the duration.

bThese high doses of codeine and meperidine are not recommended clinically.

cEquianalgesic data not available for hydrocodone.

d For opioid-tolerant patients converted to methadone, starting doses should be 10%–25% of the equianalgesic dose. Also, the half-life

of methadone can vary widely, from 12 to 190 hours.

e1 g/hour transdermally is approximately equal to morphine 2 mg/24 hours orally.

Whether patients at risk for addiction should be excluded from opioid therapy is controversial. Current evidence suggests

that such patients do well in controlled programs and should not be denied opioid treatment of pain solely on the basis of

existing addiction comorbidities. A written agreement may be helpful for obtaining informed consent about the risks and

benefits of opioid therapy and setting out terms of use, including the following:

Obtaining opioids only from a single provider

Reporting lost or stolen drugs promptly

Not using more than is prescribed or requesting early refills on a regular basis

Testing urine periodically to determine that opioids are being taken by the patient (and not diverted for economic gain) and that

illicit drugs are not being taken

Some experts recommend a universal precautions approach for all patients receiving opioids because clinical factors are

not sufficiently predictive of who will have problems with abuse or addiction. At each visit, the clinician should document

the “4 As” (McCarberg and Passik 2005):

Analgesic (pain relief)

Activities of daily living (physical and psychosocial functioning)

Adverse effects (side effects)

Aberrant drug taking (taking more than prescribed, diversion, etc.)

Long-acting opioidsPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Chou (2008) conducted an evidence-based review of 25 randomized trials (N = 2,752) that evaluated long-acting opioids

in patients with chronic noncancer pain. The review included 2 or more clinical trials of transdermal fentanyl and

long-acting oral oxycodone, morphine, codeine, and dihydrocodeine. Methadone and levorphanol were each studied in only

a single trial, and no trials evaluated long-acting hydromorphone. Only 5 trials compared one long-acting opioid with

another; 7 compared a long-acting opioid with a short-acting opioid, and 13 compared a long-acting opioid with a

nonopioid agent or placebo. Ten trials used a crossover design. The number of subjects in the trials averaged 110 (range,

12–680). The pain disorder was osteoarthritis in 5 trials, back pain in 7, neuropathic pain in 7, heterogeneous pain

conditions in 4, phantom limb pain in 1, and chronic pancreatitis in 1. Nearly all of the trials were of relatively short

duration, ranging from 5 days to 16 weeks. All trials excluded persons with past or current substance abuse. The majority

of trials recruited patients from specialty clinics, most commonly from rheumatology or pain practices.

The authors concluded that there is insufficient evidence from either the 20 trials comparing long-acting opioids with other

types of drugs or with placebo or the 5 head-to-head trials to suggest that one long-acting opioid is superior to another.

The largest (680 subjects) and longest (13 months) randomized trial found that transdermal fentanyl and twice-daily

morphine were similar in efficacy for patients with chronic low back pain who had not previously received strong opioids

on a regular basis (Allan et al. 2005). Also, the 7 trials comparing long- versus short-acting opioids were unable to

demonstrate superior efficacy or lesser side-effect rates with long-acting opioids. The single fair-quality trial comparing

differences in adverse events among long-acting opioids found less constipation with fentanyl than with morphine (31%

1. 48%) but also a trend toward a higher rate of withdrawals due to any adverse event with fentanyl (37% vs. 31%).

Methadone

Until recently, methadone has been used primarily as maintenance drug to prevent withdrawal in opioid-addicted adults.

The stigma as a “drug for addicts” has been one factor limiting its use as an analgesic in clinical practice. It has gained

increased use in the treatment of intractable pain in end-of-life care and other palliative care settings. Concerns regarding

use of methadone for pain relate to its long and unpredictable half-life and the associated risk of a delayed overdose.

Furthermore, there are large individual variations in presumed equianalgesic doses of methadone relative to other opioids.

This prevents the use of simple equianalgesic tables to calculate the required dose of methadone during rotation from

other opioids.

Although methadone has increasingly been used for the treatment of chronic noncancer pain, published data are rather

modest. In a literature review of 21 studies, only 1 small randomized trial (N = 19) was found; the remainder were either

cases series (N = 7) or case reports (N = 13) (Sandoval et al. 2005). Methadone was administered primarily when

previous opioid treatment was ineffective or poorly tolerated. Thus, the evidence base is currently inadequate and does

not support a first-line role for methadone in chronic pain therapy.

Antidepressants

Tricyclic antidepressants and selective serotonin reuptake inhibitors

TCAs have the longest track record in the treatment of multiple pain conditions. Typically, lower doses of TCAs have been

used in clinical trials of pain (e.g., 25–100 mg of amitriptyline or equivalent) than the doses usually necessary for treating

depression. Advantages of TCAs include good evidence from multiple clinical trials, decades of clinical experience with

TCAs in pain management, and the low cost of these generic agents. Disadvantages include the side effects associated

with TCAs (which may be less, however, when prescribing the lower doses used for analgesia), including worrisome

cardiovascular side effects (e.g., hypertension, postural hypotension, arrhythmias) and a risk of falling in elderly patients,

and potential lethality in overdoses.

A meta-analysis of 96 RCTs evaluating antidepressants for the treatment of conditions manifested by somatic symptoms

(the majority involving painful symptoms) included 55 TCA trials, of which 76% showed benefits; 28 trials using

anti-serotonin agents (principally headache trials using mianserin, a drug approved in Europe but not in the United

States), of which 57% showed benefits; and 17 trials using selective serotonin reuptake inhibitor (SSRI) antidepressants,

of which 47% showed positive results (O’Malley et al. 1999). Only a few trials were head-to-head comparisons of two

antidepressants. Indirect comparisons did not show a significant difference by type of antidepressant using

meta-regression, but TCAs were superior to SSRIs (P <0.02) using a bivariate tally procedure. Admittedly, such statistical

comparisons are not as conclusive as direct comparisons of antidepressants within the same trial. Another review

concluded that SSRIs appeared to have a relatively weak effect in ameliorating chronic pain (Jung et al. 1997).

Serotonin–norepinephrine reuptake inhibitors

Duloxetine has proven superior to placebo in three 12-week randomized, placebo-controlled trials that enrolled patients

with pain due to diabetic peripheral neuropathy (Goldstein et al. 2005; Raskin et al. 2005; Wernicke et al. 2006). Both

60-mg and 120-mg daily dosages of duloxetine separated from placebo, but not from one another. Duloxetine showed no

adverse effects on diabetes control. Duloxetine showed rapid onset of action, with separation from placebo beginning at

week 1. Both patients with depression and those without depression were enrolled in the trials, although path analysis

estimated that more than 90% of the analgesic effect in duloxetine-treated patients with diabetic neuropathy was

attributable to a direct analgesic effect, with less than 10% possibly explained by an antidepressant effect (Perahia et al.

2006).

Some have questioned the strength of the evidence regarding the analgesic effect of serotonin–norepinephrine reuptakePrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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inhibitors (SNRIs). A recent meta-analysis of five trials in depressed patients reported a very small and statistically

nonsignificant (P = 0.057) analgesic effect for duloxetine (Spielmans 2008). Another meta-analysis that examined the

evidence comparing duloxetine with SSRIs in treating the painful physical symptoms of depression likewise concluded that

there was insufficient evidence of a superior analgesic effect with duloxetine (Krebs et al. 2008b). On the other hand,

placebo-controlled trials of duloxetine have shown a significant analgesic effect of duloxetine not only for neuropathic pain

but for the chronic widespread pain of fibromyalgia as well (Arnold et al. 2004, 2005, 2007b).

Several factors related to these trials should be considered. Pain was typically examined as a secondary outcome in major

depression trials, and an important proportion of patients had no pain. Thus, the depression studies were not optimally

designed to test analgesic effects. In contrast, the neuropathic pain and fibromyalgia studies were designed primarily to

examine treatment effects on pain. Of note, major depression trials in which the sample was enriched with patients

reporting at least moderate pain showed that duloxetine had an analgesic effect that was independent of its effect on

depression (Brannan et al. 2005; Brecht et al. 2007). The analgesic effect of duloxetine in the pain trials was compared

with placebo rather than with another antidepressant. Head-to-head comparisons of a particular antidepressant with an

active comparator are few, so it is harder to draw conclusions about the superiority of duloxetine or other SNRIs compared

with other antidepressants or pain treatments. In summary, there is reasonably good evidence that duloxetine is more

effective than placebo in treating neuropathic pain and fibromyalgia. Evidence regarding its separation from placebo in

treating the secondary painful symptoms of major depression is inconclusive, and its relative effectiveness for pain

compared with other antidepressants or analgesic therapies requires head-to-head clinical trials.

Other antidepressants

Mirtazapine was studied in a 6-week open-label trial of 594 patients with a primary diagnosis of at least one chronic pain

syndrome ( 3 months) and a clinical diagnosis of depression (Freynhagen et al. 2006). The mean daily dose was 35 ± 10

mg at study endpoint, and a statistically significant reduction in pain (P <0.0001) was found. Pain improvement was not

related to age or type of pain syndrome.

Anticonvulsants

Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are

useful for chronic neuropathic pain, especially when the pain is lancinating or burning. Three of the most extensively

studied anticonvulsants are gabapentin, pregabalin, and carbamazepine. Gabapentin and pregabalin have the strongest

evidence for the treatment of pain. These two gabapentinoids act as neuromodulators by selectively binding to the 2

-subunit protein of calcium channels in various regions of the brain and the superficial dorsal horn of the spinal cord. This

results in inhibition of the release of excitatory neurotransmitters that are important in the production of pain. Gabapentin

and pregabalin are analogs of -aminobutyric acid (GABA), but they have no activity at GABA receptors and do not alter

GABA uptake or degradation.

Gabapentin

A systematic review of 15 trials (1,468 participants) evaluating gabapentin included 1 acute pain trial and 14 trials

involving neuropathic pain (7 studies of diabetic neuropathy, 2 of postherpetic neuralgia, and 1 each of cancer-related

neuropathy, phantom limb pain, spinal cord injury, Guillain-Barré syndrome, and miscellaneous neuropathies) (Wiffen et

1. 2005b). In the 14 chronic neuropathic pain trials, 42% of participants improved taking gabapentin versus 19% taking

placebo, and the NNT for improvement in all trials with evaluable data was 4.3 (95% CI = 3.5–5.7). Withdrawal rates were

14% for gabapentin versus 10% for placebo. The study of acute postoperative pain (70 patients) showed no benefit for

gabapentin. Thus, there is good evidence that gabapentin is more effective than placebo in the treatment of chronic

neuropathic pain.

Pregabalin

Pregabalin is a novel compound that has analgesic, anticonvulsant, and anxiolytic effects (Shneker and McAuley 2005).

The FDA approved pregabalin for treatment of neuropathic pain associated with diabetic peripheral neuropathy and

postherpetic neuralgia and for treatment of fibromyalgia; evidence from the supporting trials is discussed in the

“Neuropathic Pain” and “Fibromyalgia” sections of this chapter. Pregabalin is also approved as an adjunctive therapy for

adults with partial-onset seizures. The U.S. Drug Enforcement Administration has placed pregabalin in Schedule V of the

Controlled Substance Act (indicating a low potential for abuse), possibly because of withdrawal symptoms that were found

during clinical trials. The most common adverse events are related to the central nervous system and include somnolence,

dizziness, and peripheral edema. Dose-related weight gain can occur, highest at a dosage of 600 mg/day. For pain

disorders, the usual dosage is 300–450 mg/day, administered in twice-daily doses.

Carbamazepine

A systematic review of 12 trials (404 participants) included 4 placebo-controlled trials of trigeminal neuralgia, of which 2

with evaluable data yielded an NNT of 1.8 (95% CI = 1.4–2.8) (Wiffen et al. 2005c). For diabetic neuropathy the data were

insufficient to calculate an NNT. There was no evidence that carbamazepine was effective for acute pain. In summary,

carbamazepine appears effective for trigeminal neuralgia, but the amount and quality of evidence for gabapentin are

stronger for other types of neuropathic pain.

Other anticonvulsants

A systematic review that included other anticonvulsants found an NNT of 2.1 (95% CI = 1.5–3.6) for phenytoin in a singlePrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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trial of diabetic neuropathic pain (Wiffen et al. 2005a). Sodium valproate was ineffective in a single trial of acute pain.

Other Pharmacological Agents

Skeletal muscle relaxants

Most skeletal muscle relaxants are approved by the FDA for treating either spasticity (baclofen, dantrolene, and

tizanidine) or musculoskeletal pain (carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and

orphenadrine) (Chou and Peterson 2005). There is insufficient evidence to prove that skeletal muscle relaxants differ in

their efficacy, adverse events, or safety. Most trials have focused on acute rather than chronic pain. Cyclobenzaprine has

been studied in several fibromyalgia trials and is discussed further in the “Fibromyalgia” section (under

“Pharmacotherapy”). Indeed, cyclobenzaprine is the best-studied muscle relaxant in musculoskeletal disorders overall; in

21 fair-quality trials, it has consistently proven superior to placebo for relieving pain, reducing muscle spasms, and

improving functional status. Cyclobenzaprine 5-mg doses are equally effective as 10-mg doses (each given three times a

day) but cause fewer side effects. Also, 20-mg doses (thrice daily) are not more effective than 10-mg doses and cause

more side effects.

Topical analgesics

A potential advantage of topical agents is avoidance of the systemic side effects often associated with oral medications.

Disadvantages are that only localized areas of pain can be effectively treated and that irritating skin reactions occur in a

minority of patients. Several topical analgesics—lidocaine, capsaicin, and salicylate—have been studied in multiple trials.

Postherpetic neuralgia is an FDA-approved indication for the lidocaine 5% patch, which is discussed in more detail in the

“Neuropathic Pain” section. In a meta-analysis of systemic administration of local anesthetics for neuropathic pain,

Tremont-Lukats et al. (2005) reviewed 19 studies (706 patients total; 10 trials of lidocaine and 9 trials of mexiletine, an

antiarrhythmic agent that is also used off-label for pain). Lidocaine (most commonly 5 mg/kg administered intravenously

over 30–60 minutes) and mexiletine (median dosage = 600 mg/day administered orally) were similar in efficacy and

tolerance to morphine, amitriptyline, and gabapentin. However, the effects of parenteral lidocaine are short lived, and

mexiletine is not yet widely used or recommended as first- or second-line therapy.

Capsaicin is an alkaloid derived from chili peppers that acts on vanilloid type 1 receptors; repeated application of capsaicin

is thought to desensitize cation channel receptors, leading to depletion of substance P from primary afferent neurons

(Chong and Hester 2007). The main disadvantage of capsaicin is the initial burning sensation, which may persist for days.

Capsaicin must be applied three to four times per day over the entire painful area for up to 8 weeks before optimal pain

relief can be achieved. Mason et al. (2004a) reviewed the clinical trial evidence for using capsaicin to treat chronic pain.

Six double-blind, placebo-controlled trials (656 patients) were pooled for analysis of neuropathic conditions, and three

double-blind, placebo-controlled trials (368 patients) were pooled for analysis of musculoskeletal conditions. In patients

with neuropathic pain, 57% of patients achieved at least 50% pain relief with capsaicin versus 42% of patients taking

placebo. In patients with musculoskeletal conditions, the response rates were 38% versus 25%. Approximately one-third

of patients experienced local adverse events with capsaicin. The authors concluded that capsaicin has moderate to poor

efficacy in the treatment of chronic musculoskeletal or neuropathic pain but may be useful as an adjunctive therapy or

sole therapy for a small number of patients who are unresponsive to, or intolerant of, other treatments.

The same authors also reviewed the evidence for topical salicylate (Mason et al. 2004b). In three trials evaluating 182

patients with acute conditions, topical salicylate was significantly more efficacious in relieving pain than placebo (NNT =

2.1; 95% CI = 1.7–2.8). In six trials evaluating 429 patients with chronic conditions, topical salicylate was also better than

placebo (NNT = 5.3; 95% CI = 3.6–10.2). However, larger, more rigorous trials tended to have negative results. Based on

limited information, the authors concluded that topical salicylates may be efficacious in the treatment of acute pain,

although trials of its use in treating musculoskeletal and arthritic pain suggested moderate to poor efficacy. Finally,

systematic reviews (J. Lin et al. 2004; Mason et al. 2004c) as well as a recent RCT suggest that topical NSAIDs may be

beneficial (ibuprofen for osteoarthritis of the knee has been studied the most) (Underwood et al. 2008).

Cannabinoids

The presence of specific high-affinity cannabinoid type 1 (CB1) receptor binding sites has been demonstrated in the central

nervous system and in certain peripheral tissues, whereas CB2 receptors are expressed in high quantities in immune

tissues and cells. Two main endogenous cannabinoids have been described, and their role in modulating pain has been

increasingly recognized. The social stigma associated with cannabinoids and the politicolegal issues related to cannabis

use for medical purposes have been barriers to research.

Nonetheless, six RCTs published since 2005 have shown promising results (Beaulieu and Ware 2007). The largest study

enrolled 502 patients with multiple sclerosis; the primary outcome was objective spasticity rather than pain. Five smaller

trials involving a total of 217 patients measured short-term outcomes (trial duration, 1–5 weeks) of five different pain

conditions, including multiple sclerosis, rheumatoid arthritis, upper motor neuron syndrome, human immunodeficiency

virus (HIV) neuropathy, and heterogeneous chronic pain. The agents studied included oral tetrahydrocannabinol in three

trials, nabilone in two trials, and smoked marijuana in one trial. Five of the six trials (including the large trial) showed

benefits.

In a recent review, Lever and Rice (2007) were more circumspect about the role of cannabinoids in chronic pain:

Preclinical studies demonstrate that cannabinoids can reduce pain response in a range of inflammatory and neuropathic painPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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models. In contrast, the clinical effectiveness of cannabinoids as analgesics is less clear. Progress in this area requires the

development of cannabinoids with a more favourable therapeutic index than those currently available for human use, and the

testing of their efficacy and side effects in high-quality clinical trials. (p. 265)

In summary, cannabinoids can be considered promising at this point but still experimental for the treatment of chronic

pain. Despite this, cannabinoids now appear as adjunctive agents in treatment guidelines for neuropathic pain in Europe

(Attal et al. 2006) and Canada (Moulin et al. 2007).

Nonpharmacological Treatments

Nonpharmacological treatments will not be discussed in detail but need to be mentioned because of their important role in

the management of chronic pain. Medications are typically targeted to the symptoms, but dysfunctional beliefs, attitudes,

coping styles, and behaviors frequently develop in patients with chronic pain and contribute to its perpetuation and their

disability. Moreover, just as in other chronic medical disorders, pharmacotherapy is necessary but not sufficient for

optimizing outcomes. For example, the patient with diabetes not only needs insulin or other hypoglycemic drugs but also

requires dietary changes, exercise, and other lifestyle modifications to achieve target blood glucose levels.

Psychotherapy and Behavioral Interventions

Cognitive-behavioral therapy

Cognitive-behavioral therapy (CBT) has by far the largest body of evidence supporting its effectiveness in the treatment of

various types of chronic pain disorders. Kroenke and Swindle (2000) reviewed 31 trials of CBT for the treatment of somatic

syndromes, of which more than half involved pain conditions, including 5 trials of back pain, 3 of irritable bowel syndrome,

3 of noncardiac chest pain, 2 of fibromyalgia, and 4 of other pain disorders. Most of those trials (14 of 17) involving pain

disorders found CBT to be beneficial. A recent update of this review found additional more recent studies confirming the

effectiveness of CBT (Jackson et al. 2006). Also, a recent systematic review of treatment for somatoform disorders (in

which multiple pain symptoms are often present) found CBT was effective in 11 of 13 RCTs (Kroenke 2007). Both group

CBT and individual CBT appeared effective, as did briefer courses of CBT (e.g., 3–6 sessions). When administered for pain

and other somatic disorders, it is important that CBT be somatically focused, having a somewhat different orientation than

CBT provided for depressive and anxiety disorders. Patients with chronic pain and other somatic syndromes present with

physical rather than psychological symptoms and often attribute their symptoms to physical disorders (i.e., medical

factors). Thus, the mental health professional accustomed to providing CBT for psychiatric disorders may require some

additional training in CBT appropriate for treating chronic pain and other somatic syndromes.

Pain self-management programs

Pain self-management (PSM) programs that emphasize self-efficacy have consistently demonstrated effectiveness in

improving health outcomes and reducing health care utilization among patients with various rheumatic conditions (Heuts

2005; Lorig 2003; Lorig and Holman 1993); benefits included cost-effectiveness (Lorig and Holman 1993) and improved

psychological functioning (Barlow et al. 1998). Self-management for both acute (Damush et al. 2003) and chronic (Von

Korff and Moore 2001) low back pain has also proven effective. Indeed, CBT and PSM are the two best-established

psychobehavioral approaches to treating chronic musculoskeletal pain (Bradley and Alberts 1999). In fact, PSM

incorporates important components of CBT with additional educational and behavioral strategies. Another important

component of PSM programs is emotional coping and management (Lorig and Holman 2003). One advantage of PSM

compared with CBT in the medical setting is that it may be effectively administered by varying levels of trained

individuals, including lay personnel (Cohen et al. 1986).

Hypnosis

A systematic review of hypnosis found that its effects on chronic pain tend to be similar, on average, to the effects of

progressive muscle relaxation, biofeedback, and other types of relaxation training, all of which often include hypnosis-like

suggestions (Jensen and Patterson 2006). None of the published studies have compared hypnosis with an equally credible

placebo or minimally effective pain treatment. Therefore, conclusions cannot yet be made about whether hypnotic

analgesia treatment is specifically effective over and above patients’ expectancies.

Other psychological interventions

Other reviews of psychological interventions for pain have shown a similar predominance of CBT trials. A meta-analysis of

27 RCTs of psychological interventions for treating arthritis found that CBT was used in 23 trials, stress management in 5,

and biofeedback, emotional disclosure, and hypnosis in 1 trial each (several trials used more than one intervention) (Dixon

et al. 2007). The reduction in pain was statistically significant but clinically rather small (pooled effect size, 0.18). Three

systematic reviews of psychological treatments for somatic syndromes (many of which are manifested predominantly by

pain) have also been heavily weighted with CBT studies (Allen et al. 2002; Henningsen et al. 2007; Raine et al. 2002). A

large trial (N = 1,337 patients) of telephone-based, nurse-administered problem-solving therapy (which is one of the

evidence-based psychotherapies for depression) proved the therapy beneficial in primary care patients with chronic pain

(Ahles et al. 2006), although further research is needed before one could recommend this over CBT or PSM programs.

Exercise

Exercise has been extensively studied in chronic pain patients and has been demonstrated to be an effective adjunctive

treatment for several types of chronic pain disorders. Evidence regarding its effectiveness is discussed in more detail inPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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the “Fibromyalgia” and “Osteoarthritis” sections. Six general issues relevant to initiating and maintaining an exercise

program for chronic pain are summarized in Table 66–2.

TABLE 66–2. Key principles for initiating and maintaining exercise for chronic pain

Principle Comments

Type of exercise Aerobic exercise is particularly important for some types of chronic pain (e.g., fibromyalgia), whereas strengthening

and flexibility exercises may be helpful in others (back pain, osteoarthritis).

Catastrophizing

as a barrier

Fear that movement or activity will worsen pain is common. Emphasizing that gradual activity will not cause further

harm but instead can be beneficial is essential to activation and rehabilitation.

Stage of change For patients in precontemplation phase, motivating them to initiate exercise is the challenge. For many others who

begin an exercise program, getting them to maintain regular exercise more than a few months is the critical issue.

This is analogous to weight loss, smoking cessation, and other lifestyle or behavioral changes.

Graduated

program

Patients should not try to do too much initially. Instead, they should begin slowly and increase the amount of

exercise gradually over a matter of weeks to months.

Structured vs.

home based

The benefits of structured exercise programs demonstrated in some research studies may have a “voltage drop”

when patients are instructed to begin an exercise program on their own. Exercise conducted in clinical settings

(e.g., physical therapy, rehabilitation programs) or community settings (e.g., YMCA, fitness centers) may be

reinforced by motivation, group participation, expert leadership, guidance, and/or an externally imposed regular

schedule.

Monotherapy vs.

bundled

Many studies of exercise have included other components, such as education about the particular pain disorder,

self-management techniques, relaxation, and other cognitive-behavioral strategies. Certainly, exercise coupled with

one or more of these is ideal.

Complementary and Alternative Medicine

A comprehensive review of CAM therapies for chronic pain was recently published (Tan et al. 2007). Although it is beyond

the scope of this chapter to discuss this subject in detail, the authors concluded there was reasonable evidence for the

effectiveness of the following therapies:

Acupuncture for chronic low back pain and probably premenstrual syndrome–related pain

Massage therapy for low back and shoulder pain

Chiropractic therapy for several types of musculoskeletal pain

Yoga for low back pain

Meditation (as well as hypnosis) for several types of chronic pain

Two CAM treatments in particular—acupuncture and the use of magnets—have been the topic of several recent systematic

reviews (Table 66–3). Acupuncture has proven effective in treating back pain and possibly osteoarthritis of the knee,

although osteoarthritis trials have been fewer and the results less conclusive (Manheimer et al. 2005, 2007; A. White et al.

2007). Although headache pain is not the focus of this chapter, it should be noted that a systematic review of 13 trials of

acupuncture for migraine headaches found inconclusive evidence supporting its efficacy, although most studies had

serious design limitations (Griggs and Jensen 2006). Acupuncture’s effects on experimental pain appear to be mediated

through the release of neurohormonal factors, some of which can be inhibited by the opioid antagonist naloxone (Staud

2007). Compared with the pain relief associated with placebo use, acupuncture-related pain relief takes considerable time

to develop and to wear off.

TABLE 66–3. Acupuncture and magnets for painful disorders: summary of systematic reviews

Treatment Study Condition Review type

(N)

Benefits Strength

of

evidence

Comments

Acupuncture

Acupuncture Manheimer

et al. 2005

Back pain Meta-analysis

(33 trials)

Yes Good Acupuncture was more effective than sham

acupuncture (ES = 0.54) or no treatment (ES =

0.69) in chronic low back pain.

Acupuncture Manheimer

et al. 2007

Knee OA Meta-analysis

(11 trials)

Mixed Moderate Acupuncture was more effective than wait-list (ES =

0.96) or usual-care controls but only slightly more

effective than sham acupuncture for short-term (ES

= 0.35) and long-term (ES = 0.13) pain

improvement.

Acupuncture A. White et

1. 2007

Knee OA or

pain

Meta-analysis

(13 trials)

Yes Moderate In 5 studies that could be combined (N = 1,334),

acupuncture was superior to sham acupuncture for

pain and function and was also superior to

no-intervention controls.

MagnetismPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Treatment Study Condition Review type

(N)

Benefits Strength

of

evidence

Comments

Static

magnets

Eccles 2005 Various Systematic (21

trials)

Yes Moderate Eleven of 18 better-quality trials were positive.

Multiple types of pain conditions were studied.

Static

magnets

Pittler et al.

2007

Various Meta-analysis

(25 trials)

No Moderate Meta-analysis showed no significant effects.

Evidence was encouraging only for one

condition—osteoarthritis.

PEMF

stimulation

McCarthy et

1. 2006

Knee OA Systematic

(five trials)

No Moderate PEMF therapy yielded insignificant improvement in

pain and function.

Note. ES = effect size (mean difference between groups divided by pooled standard deviation); OA = osteoarthritis; PEMF = pulsed

electromagnetic field.

Static magnets represent a multibillion-dollar industry (Pittler et al. 2007). As many as one-quarter of patients with

rheumatoid arthritis, osteoarthritis, or fibromyalgia use magnets or copper bracelets for pain relief. The mechanisms for

magnets’ putative efficacy are not established. One theory is that magnetic fields attenuate nociceptive C-fiber

depolarization by shifting the membrane resting potential. Another theory suggests that magnetic fields promote an

increase in blood flow through the skin and subcutaneous and muscular tissues, which reduces pain. However, the

empirical data for efficacy are inconclusive. A qualitative review found that static magnets were effective across a variety

of pain conditions (Eccles 2005). However, a quantitative meta-analysis found no significant effects of static magnets,

except possibly (though not conclusively) in treating osteoarthritis (Pittler et al. 2007). Pulsed electromagnetic energy has

been much less studied and in a review of five trials was found ineffective (McCarthy et al. 2006).

Combination Therapy

Over time, the treatment of chronic pain often includes stepwise addition to a patient’s regimen (and deletion if a therapy

shows no benefit) of medications from several classes (Black and Sang 2005; Gallagher 2005). In addition to medications

given to produce analgesia, pain management may include medications to treat the side effects of the analgesics, such as

laxatives or stool softeners for patients receiving opioids, gastroprotective medications for those receiving NSAIDs, and

psychostimulants to combat excessive somnolence.

Very few studies have tested combinations of treatments to determine their additive value, if any, compared with

monotherapy. Only limited data suggest that the combination of acetaminophen with NSAIDs has additive pain-relieving

effects (Schug 2005). More data show a beneficial effect in combining acetaminophen with opioids, including codeine,

tramadol, and morphine. Indeed, one of the more common fixed combinations in a single pill has been the coupling of an

opioid, such as codeine, tramadol, oxycodone, or hydrocodone, with a nonopioid analgesic such as acetaminophen or

aspirin. One important consideration in using fixed-dose combinations is that the maximum daily dosages of one

component may restrict flexibility in optimizing the dosage of the other component. For example, when oxycodone 5 mg is

combined with acetaminophen 500 mg, the maximum number of tablets that can be administered is eight in a 24-hour

period (i.e., 4,000 mg of acetaminophen). If this is insufficient to manage the patient’s pain, the opioid and nonopioid

should be given as separate medications to allow further upward titration of the opioid.

Head-to-head clinical trials comparing different analgesics, separately or in combination, are rare. One example is a small

(57 subjects enrolled; 41 trial completers) randomized, double-blind crossover trial in patients with neuropathic pain,

which showed that gabapentin and morphine combined achieved better analgesia at lower doses of each drug than either

as a single agent (Gilron et al. 2005). On the other hand, the gabapentin–morphine combination resulted in a higher

frequency of constipation than gabapentin alone and a higher frequency of dry mouth than morphine alone.

The common decision in clinical practice when optimal pain relief has not been achieved is whether to switch to a new

treatment or to add it to what is currently being provided. Given the paucity of combination drug trials, this decision is

currently guided by practical considerations. Switching to another monotherapy is often less costly than combining two or

more treatments and often is done when a patient has had only a minimal response to and/or poor tolerance of the initial

treatment. On the other hand, adding a second treatment may be favored when there has been at least a partial response

to the first therapy or when the second treatment has a different mechanism of action that may complement the original

treatment. Factors influencing combination therapy decisions include not only added efficacy but also costs, side effects,

adherence, and patient preferences. Sometimes, the secondary effects of a drug may influence the decision to use it in a

particular patient. For example, the side effect of sedation that occurs with certain medications (e.g., gabapentin or

pregabalin) may be troublesome in one patient whereas in another it may be useful to treat comorbid insomnia,

particularly if taken at bedtime. Likewise, the antidepressant effects of a particular adjunctive pain medication (e.g.,

SNRIs like duloxetine or venlafaxine) may reduce both pain and mood disturbances in the patient with diabetic

neuropathic pain and comorbid major depression. TCAs could serve the same purpose, although higher doses of TCAs are

typically required for antidepressant action than for analgesic action, in which case the side effects of higher-dose TCAs,

especially their cardiovascular effects, must be considered as well.

SELECTED PAIN DISORDERS

Neuropathic Pain

Chou et al. (2007a) summarized several key points regarding the prevalence, etiology, and classification of neuropathicPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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pain:

Neuropathic pain (NP) is often classified by etiology or by the presumed site of neurologic involvement (central or peripheral).

More complex classification systems based on symptoms, signs, anatomical distribution, or hypotheses regarding etiologies have

been proposed, but it is not clear if such classifications are accurate or reproducible. NP is characterized by continuous or

intermittent spontaneous pain, typically characterized by patients as burning, aching, or shooting. Up to 3% of the general

population reports NP at some time. NP is most commonly associated with painful diabetic neuropathy, post-herpetic neuralgia

(PHN), or lumbar nerve root compression. Diabetic neuropathy occurs in approximately 10% of persons with diabetes. The most

common form of diabetic peripheral neuropathy is a distal symmetric polyneuropathy, typically manifested by symptoms beginning

in the feet. PHN is defined as pain persisting or recurring at the site of acute herpes zoster 3 or more months after the acute

episode. It occurs in up to 25% of patients following an episode of shingles. Symptomatic spinal stenosis and lumbar disc

herniation with nerve root compression occur in approximately 3% and 4% of patients with low back pain, respectively. Other

causes of NP include cancer-related pain, spinal cord injury, post-stroke pain, HIV-associated neuropathy, and phantom limb pain.

Uncommon but potentially debilitating NP conditions include trigeminal neuralgia (incidence 4/100,000 population). In the U.S.,

health care and disability-related costs associated with NP are estimated at almost $40 billion annually. (Chou et al. 2007a, p. 6)

Four drugs are FDA approved for the treatment of diabetic neuropathy or postherpetic neuralgia: gabapentin, pregabalin,

duloxetine, and lidocaine (the lidocaine patch) (Chou et al. 2007a). Recommendations regarding the dosing of these drugs

for neuropathic pain are summarized in Table 66–4. Venlafaxine and lidocaine gel also have some evidence for efficacy in

treatment of neuropathic pain but do not have an FDA indication for this use. Other drugs have been used for neuropathic

pain—particularly TCAs and anticonvulsants—besides those listed above, but have not been approved by the FDA for this

indication. The one exception is carbamazepine, which was approved to treat trigeminal neuralgia based on three trials

that included a total of 150 patients, published in the 1960s.

TABLE 66–4. First-line drugs for neuropathic pain

Drug Trade

name

Labeled

indication

Recommended daily dosage for neuropathic

pain

Daily dosage range in

RCTs (median)

Anticonvulsants

Gabapentin Neurontin Postherpetic

neuralgia

Start at 300 mg, titrate to 900 mg, increase up to

1,800 mg (in three doses)

900–3,600 mg (1,800 mg)

Pregabalin Lyrica Diabetic

neuropathy

Postherpetic

neuralgia

Start at 150 mg, increase up to 300 mg (in two to

three doses)

75–600 mg (300 mg)

SNRI antidepressants

Duloxetine Cymbalta Diabetic

neuropathy

60 mg once daily

20–120 mg (90 mg)

Topical

analgesic

Lidocaine 5%

patch

Lidoderm Postherpetic

neuralgia

Up to three patches for up to 12 hours within a

24-hour period

1–3 patches

Note. NA = not applicable; RCTs = randomized, controlled trials; SNRI = serotonin–norepinephrine reuptake inhibitor.

In their evidence-based review commissioned by the Agency for Healthcare Research and Quality, Chou et al. (2007a)

highlighted several key findings:

1. Gabapentin (12 trials), pregabalin (8 trials), and duloxetine (3 trials) have proven superiority to placebo.
2. Trials of topical lidocaine patch or gel and venlafaxine are inconclusive.

Although indirect comparisons suggest the potential superiority of TCAs compared to gabapentin, direct analyses of 3

head-to-head trials found no difference between gabapentin and TCAs for pain relief, though the estimates are relatively

imprecise. Additionally, 1 small trial found no difference between venlafaxine and imipramine.

3.  

Indirect analyses of trials found gabapentin and pregabalin moderately superior to both other anticonvulsants (carbamazepine,

lamotrigine, topiramate, and valproic acid) and SSRIs. However, such indirect analyses must be interpreted cautiously.

4.  

Chou et al. (2007a) also summarized the results of 6 systematic reviews that evaluated the benefits of gabapentin,

pregabalin, SNRIs, or topical lidocaine for neuropathic pain. All of the newer medications for neuropathic pain were

superior to placebo in at least one systematic review. The systematic reviews included a total of 17 unique

placebo-controlled trials of gabapentin, 5 trials of pregabalin, 3 trials of venlafaxine, 6 trials of topical lidocaine, and 2

trials of duloxetine. None of the systematic reviews found any published reports of a head-to-head trial of one of these

drugs versus another. Several of the reviews also concluded that TCAs were effective (the best evidence was for

amitriptyline), and there were limited data for the effectiveness of SSRIs. It should also be noted that many of the TCA

studies performed several decades ago had smaller samples than trials of currently approved drugs. For example, the sum

total of patients with diabetic neuropathy studied in all TCA trials was less than 120 (Chong and Hester 2007). Also, a

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Eisenberg et al. (2006) conducted a systematic review of trials evaluating the use of opioids for neuropathic pain. Of 23

trials, 14 were classified as short-term (<24 hours), and 9 as intermediate-term (median, 28 days; range, 8–70 days). The

short-term trials had contradictory results. In contrast, all 9 intermediate-term trials demonstrated opioid efficacy: 13

points lower (95% CI = –16 to –9) than placebo on a scale of 1–100.

The European Federation of Neurological Sciences published guidelines on pharmacological treatment of neuropathic pain

in 2006 (Attal et al. 2006), which are generally concordant with the Agency for Healthcare Research and Quality

evidence-based report. The European Federation of Neurological Sciences concluded that there was level A evidence for

the efficacy of TCAs, gabapentin, pregabalin, and opioids in neuropathic pain, followed by topical lidocaine in postherpetic

neuralgia and SNRIs in diabetic neuropathy. They also concluded that diabetic and nondiabetic painful polyneuropathies

are similar in symptomatology and response to treatment. The only exceptions noted were that HIV- and

chemotherapy-induced neuropathy may be more refractory to treatment. The principal opioids studied have been

oxycodone and tramadol, both of which have proven superior to placebo. Trials of topical capsaicin have provided

discrepant results. The antiarrhythmic drug mexiletine, the N-methyl-D-aspartate antagonist memantine, and topical

capsaicin have not shown convincing efficacy.

A consensus panel from the IASP likewise concluded that first-line treatments for neuropathic pain include certain

antidepressants (i.e., TCAs and SNRIs), calcium channel 2 -ligands (i.e., gabapentin and pregabalin), and topical

lidocaine (Dworkin et al. 2007). Opioid analgesics and tramadol were recommended as second-line treatments. The IASP

also noted: “Although few clinical trials have been conducted, no medications have demonstrated efficacy in patients with

lumbosacral radiculopathy, which is probably the most common type of neuropathic pain” (Dworkin et al. 2007, p. 237).

Indeed, an RCT evaluating nortriptyline, morphine, and their combination in patients with chronic lumbar root pain found

no greater efficacy with the combination than with either medication alone or placebo (Khoromi et al. 2007). The IASP

also noted that little is known regarding the treatment response of those with mild to moderate neuropathic pain because

most trials have enrolled patients with more severe neuropathic pain, and long-term effectiveness is unknown because

most RCTs have been of less than 3 months’ duration. The IASP also favored secondary-amine TCAs (nortriptyline and

desipramine) over tertiary-amine TCAs (amitriptyline and imipramine) because of their comparable analgesia (Max et al.

1992; Rowbotham et al. 2005; Watson et al. 1998) and fewer side effects. Finally, the IASP concluded that the magnitude

of pain reduction associated with opioid analgesics is at least as great as that obtained with other treatments for

neuropathic pain.

No clear first choice emerges among FDA-approved drugs for neuropathic pain. The most common adverse events for

gabapentin and pregabalin include dizziness, somnolence, and weight gain, and nausea can be a perplexing side effect of

SNRIs. Sometimes, a drug may be preferentially chosen because of comorbid conditions (e.g., gabapentin or pregabalin for

the patient with neuropathic pain and insomnia, or duloxetine when neuropathic pain is accompanied by major

depression). Also, lower doses of two drugs may produce better analgesia with fewer side effects in selected patients

(Gilron et al. 2005). Finally, switching or adding medications will frequently be necessary because no more than

40%–60% of patients obtain partial relief from a single agent (Dworkin et al. 2007).

Fibromyalgia

Mechanisms and Evaluation

Fibromyalgia is one of the most common musculoskeletal disorders seen in rheumatology practice as well as primary care.

It is often classified among the functional somatic syndromes (FSSs), which include irritable bowel syndrome, chronic

fatigue syndrome, temporomandibular joint disorder, interstitial cystitis, and other symptom-based conditions manifested

by a cluster of symptoms for which the pathophysiological mechanism is not well understood (Aaron and Buchwald 2001).

Patients with one FSS often suffer from one or more other FSSs as well as psychological comorbidity, including depression,

anxiety, and histories of abuse during childhood or as adults. The distinction between FSS and somatoform disorders is

also being revisited (Kroenke et al. 2007). However, it does not appear that FSSs are entirely explained by psychological

factors (Henningsen et al. 2003), and emerging research also shows biological factors that may be causative or

contributory.

The American College of Rheumatology core diagnostic criteria for fibromyalgia are quite simple and do not require any

laboratory or radiological testing. They are twofold:

Generalized pain that is both widespread (i.e., on both the right and left sides of the body, upper and lower halves, and axial as

well as proximal arms and legs) and chronic (lasting 3 months)

1.  

Multiple tender points on physical examination (located in the front and back of the neck, upper chest and back areas, iliosacral

and posterior gluteal areas, elbows and knees)

2.  

Although the American College of Rheumatology criteria technically require a tender point threshold ( 11 of 18), many

clinicians do not actually count tender points but rather establish that the patient is tender at multiple areas, which can be

done in 5–10 seconds. Besides multiple tender points, the other diagnostically useful finding is that, unlike patients with

arthritic conditions (e.g., osteoarthritis, rheumatoid arthritis, systemic lupus) who mainly suffer from arthralgias (pain and

tenderness over the joints or periarticular regions), fibromyalgia patients experience myalgias (pain and tender points in

nonarticular regions). In fact, recent research shows that fibromyalgia patients feel tenderness wherever you apply

pressure, including areas previously considered to be “control points” (Clauw 2007). The tenderness simply reflects the

fibromyalgia patient’s tendency toward allodynia (experiencing pain from stimuli that would normally be nonpainful) orPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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hyperalgesia (experiencing more severe pain from stimuli that would normally be only mildly painful). Given that the

symptoms seem to arise from disturbances in the central processing of pain and that tender points are a relatively

nonspecific finding, some have recently advocated calling the condition chronic widespread pain.

The primary problem in fibromyalgia appears to be not that there is too much input coming from the pressure nociceptors

peripherally but rather that there is inadequate filtering of that activity, perhaps because of decreased activity of

descending anti-nociceptive pathways. In fact, multiple mechanisms seem to be operative in fibromyalgia (Abeles et al.

2007). Two key mechanisms are as follows:

Functional imaging studies in fibromyalgia patients have shown increased blood flow to pain-relevant areas of the brain at lower

thresholds of nociceptive input.

1.  

There appears to be dysregulation of descending inhibitory pain pathways. Thus, the pain “amplifier” is turned up, and the “mute”

button is turned down in fibromyalgia patients. Collectively, this is known as central sensitization.

2.  

Not only is fibromyalgia accompanied by psychiatric comorbidity, it also can coexist with other rheumatological disorders.

For example, as many as one-quarter of patients with rheumatoid arthritis and other systemic arthritides may also have

fibromyalgia. Thus, if an individual with arthritis or another musculoskeletal disorder also has chronic widespread pain,

therapies effective for fibromyalgia should be added to the treatment regimen. Also, communication with the patient,

including explanations about central sensitization and abnormal pain processing, may be helpful. Despite assumptions that

being “labeled” with fibromyalgia may adversely affect patients, it has been shown that patients have had significant

improvement in health satisfaction and symptoms after having received this diagnosis (K. P. White et al. 2002).

Pharmacotherapy

Five types of medications are effective in fibromyalgia: 1) TCAs, 2) cyclobenzaprine, 3) tramadol, 4) SNRIs (duloxetine,

milnacipran), and 5) 2 -ligand anticonvulsants (pregabalin, gabapentin). Although classified as a muscle relaxant,

cyclobenzaprine has a chemical structure closely related to that of the TCAs, which may partly account for its effectiveness

in fibromyalgia. Although multiple trials have shown the effectiveness of tramadol in fibromyalgia, the few studies of

stronger opioids have not established their efficacy. Also, the few studies of NSAIDs in fibromyalgia have also had

negative results, suggesting that a class of drugs considered first-line treatment for arthritis and other musculoskeletal

disorders may not be effective in treating fibromyalgia.

Perhaps because clinicians are more familiar with traditional analgesics than with medications proven effective in treating

fibromyalgia, there is a disconnect between current practice and evidence. This was highlighted by Clauw (2007):

Market surveys suggest that the no. 1 class of drugs currently used to treat fibromyalgia in the United States is NSAIDs, whereas

opioids are no. 3 or 4, even although there is no evidence that either of these classes of drugs works in fibromyalgia. Moreover,

most fibromyalgia patients are not being given adequate education about their disease, nor are they given access to exercise and

cognitive-behavioral therapy programs. So it should not be surprising that these patients are frustrated and trying to prove that

they really have something wrong with them when they come in to see us. (Clauw 2007, p. 107)

A meta-analysis of antidepressants published in 2000 found 13 trials with evaluable data involving three classes of

antidepressants: TCAs (9 trials), SSRIs (3 trials), and S-adenosyl-L-methionine (2 trials) (O’Malley et al. 2000). Overall,

antidepressants were superior to placebo, with an NNT of 4. The effect sizes for pain, fatigue, sleep, and overall well-being

were all moderate (range = 0.39–0.52). In the 5 studies where there was adequate assessment for treatment response

independent of depression, only 1 study found a correlation between symptom improvement and depression scores.

Antidepressant class did not make a difference, although only 3 trials tested SSRIs. Since this meta-analysis, 2 more trials

of SSRIs in fibromyalgia have been published: a flexible-dose trial showing that fluoxetine (mean dosage = 45 mg/day)

was superior to placebo in 60 women (Arnold et al. 2002), and an inconclusive trial of citalopram in 40 patients

(Anderberg et al. 2000). There is more conclusive evidence for TCAs in treating fibromyalgia than for SSRIs; however,

evidence for the superiority of TCAs compared with SSRIs in treating this condition is not as convincing as the evidence for

their superiority in treating neuropathic pain.

A meta-analysis of 4 trials found that cyclobenzaprine (10–40 mg/day) was also superior to placebo (Arnold et al. 2000).

Again, this is not surprising, given that its structure and pharmacological properties are quite similar to those of the TCAs.

Finally, 2 trials—with 100 patients (Russell et al. 2000) and 313 patients (Bennett et al. 2003), respectively—showed that

tramadol was superior to placebo in treating fibromyalgia, although the largest trial combined tramadol with

acetaminophen.

The most research in terms of pharmacotherapy for fibromyalgia over the past 5 years has involved the SNRI

antidepressants and the 2 -ligand anticonvulsants (Table 66–5). Pregabalin, duloxetine, and milnacipran have each

proven effective in several positive Phase III RCTs (Arnold et al. 2004, 2005, 2007b; Clauw et al. 2007a, 2007b; Crofford

et al. 2005; Gendreau et al. 2005; Russell et al. 2008). Pregabalin and duloxetine are the first FDA-approved drugs for the

treatment of fibromyalgia, and the makers of milnacipran will be seeking approval. Gabapentin, another 2 -ligand, has

been evaluated in a single trial, the results of which were positive (Arnold et al. 2007a). Another SNRI, venlafaxine, was

tested in a low-dose trial (75 mg/day) and did not differ in efficacy from placebo (Zijlstra et al. 2002). Certainly, the

strongest evidence exists for pregabalin, duloxetine, and milnacipran. Pregabalin and duloxetine (as well as milnacipran if

FDA approval is obtained) could be considered first-line pharmacotherapies for fibromyalgia, along with TCAs,

cyclobenzaprine, and tramadol. Given their longer track record, evidence of efficacy, and low cost, TCAs or

cyclobenzaprine might be tried initially, assuming that the patient does not have any contraindications. Tramadol could bePrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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a second-line choice, although the fact that it is a weak opioid should be taken into consideration. Generic gabapentin and

venlafaxine would be less expensive than the other drugs shown in Table 66–5, although there is only a single trial

supporting the use of gabapentin and no positive RCT results for venlafaxine.

TABLE 66–5. Efficacy of SNRI antidepressants and anticonvulsants in fibromyalgia: summary of randomized,

placebo-controlled clinical trials

Drug Study

N

Study duration

(weeks)

Primary endpoint

Beneficial?

Pregabalina Crofford et al.

2005

529 8 Mean pain score

Yes

Pregabalina Arnold et al.

2007cb

750 14 Mean pain score

Yes

Duloxetinea Arnold et al. 2004 207 12 Fibromyalgia Impact Questionnaire (total and pain scores) Yes

Duloxetinea Arnold et al. 2005 354 12 Brief Pain Inventory (average pain severity) Yes

Duloxetinea Russell et al.

2008

520 26 Brief Pain Inventory (average pain severity)

Patient Global-Rated Improvement

Yes

Milnacipran Gendreau et al.

2005

125 12 Pain intensity (pain diary) Average daily pain score Yes

Milnacipran Clauw et al.

2007bb

888 24 Composite (pain severity plus global improvement plus

physical function)

Yes

Milnacipran Clauw et al.

2007ab

1,196 24 Composite (pain severity plus global improvement) Yes

Gabapentin Arnold et al.

2007a

150 12 Brief Pain Inventory (average pain severity) Yes

Note. SNRI = serotonin–norepinephrine reuptake inhibitor.

aPregabalin and duloxetine are U.S. Food and Drug Administration (FDA)–approved for the treatment of fibromyalgia. It is expected that

applications for FDA approval of milnacipran will be submitted in 2009.

b Presented in abstract form but not yet published.

In the Phase III trials summarized in Table 66–5, pregabalin dosages were 300–450 mg/day (divided into twice-daily

doses), duloxetine dosages were 60–120 mg once a day, and milnacipran dosages were 100–200 mg once a day. In all

trials, the difference in efficacy between the highest and lowest dosages of each drug was small to minimal, whereas

side-effect rates increased somewhat at higher dosages. Thus, the majority of fibromyalgia patients who respond to these

drugs will do so with 300 mg of pregabalin, 60 mg of duloxetine, or 100 mg of milnacipran per day. The most bothersome

side effect of duloxetine and of milnacipran (as well as venlafaxine) is nausea, which may be lessened by starting therapy

at lower dosages (e.g., duloxetine 30 mg/day or venlafaxine 37.5 mg/day) for the first 1–2 weeks and by taking the drug

with food. The most bothersome side effects with pregabalin and gabapentin are somnolence (which often improves with

treatment and may be reduced by using low initial doses and having the patient take the only dose or the highest dose at

bedtime), dizziness, and weight gain.

Nonpharmacological Treatment

More than with most other pain disorders, nonpharmacological treatment for fibromyalgia is especially important, and few

patients should be treated with medication only. Several systematic reviews have shown that the three treatments with

the most evidence of efficacy are exercise (particularly aerobic exercise), education about fibromyalgia (either individually

or in groups), and CBT (Goldenberg et al. 2004; Henningsen et al. 2007; Sim and Adams 2002; van Koulil et al. 2007). A

systematic review of 34 RCTs (involving 2,276 subjects) evaluated exercise in fibromyalgia and found that aerobic-only

exercise had moderate positive effects on global well-being (effect size, 0.49), physical function (effect size, 0.66), and

pain (effect size, 0.65) (Busch et al. 2007). Strength and flexibility exercises were underevaluated. A review of 8 RCTs of

balneotherapy (pool exercise) also showed beneficial results in fibromyalgia (Gowans and deHueck 2007), and this may be

an alternative as an initial form of exercise for individuals with arthritis, to reduce weight bearing on arthritic joints, or for

patients who fear exercise will exacerbate their pain. Seven RCTs of CBT (2 of which also included exercise) involving a

total of 595 patients showed benefits for CBT in 5 of the 7 trials (van Koulil et al. 2007). Education about fibromyalgia has

been studied in numerous trials, both individually and coupled with one or more other interventions, and appears to have

a positive effect (Goldenberg et al. 2004; Sim and Adams 2002). Education coupled with exercise seems a particularly

valuable bundled intervention (Burckhardt 2006; Karjalainen et al. 2000; Rooks et al. 2007). Educational and

self-management resources are readily available online from organizations like the National Fibromyalgia Association, the

American College of Rheumatology, and the Arthritis Foundation. Finally, there are insufficient data to recommend

acupuncture, chiropractic therapy, massage therapy, trigger point injections, or other nonpharmacological or CAM

treatments for fibromyalgia (Goldenberg et al. 2004; Henningsen et al. 2007; Mayhew and Ernst 2007; Sim and Adams

2002; Tan et al. 2007).

Low Back PainPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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A series of systematic reviews by Chou and colleagues (Chou and Huffman 2007a, 2007b; Chou et al. 2007b) provides a

comprehensive update on the evaluation and management of low back pain. The authors describe the burden of back pain:

Low back pain is the fifth most common reason for all physician office visits in the U.S. and the second most common symptomatic

reason. Approximately one quarter of U.S. adults reported having low back pain lasting at least 1 whole day in the past 3 months,

and 7.6% reported at least 1 episode of severe acute low back pain within a 1-year period. Low back pain is also very costly: Total

incremental direct health care costs attributable to low back pain in the U.S. were estimated at $26.3 billion in 1998. In addition,

indirect costs related to days lost from work are substantial, with approximately 2% of the U.S. work force compensated for back

injuries each year. (Chou et al. 2007b, p. 478)

The authors go on to describe several other key points relevant to the clinical epidemiology of low back pain. Most low

back pain (85%) is nonspecific—that is, it cannot be attributed to a specific disease or spinal abnormality. Classification

schemes frequently conflict with one another, and there is little evidence that labeling patients by using specific

anatomical diagnoses improves outcomes. In a primary care setting, low back pain is only occasionally caused by a

specific serious disorder, such as cancer (0.7% of cases), compression fracture (4%), or spinal infection (0.01%). The

estimated prevalence of ankylosing spondylitis in primary care patients ranges from 0.3% to 5%. Spinal stenosis and

symptomatic herniated disc are present in about 3% and 4% of patients, respectively. The cauda equina syndrome, due to

massive midline disc herniation, is very rare (occurring in 0.04% of patients with low back pain). Urinary retention is 90%

sensitive, and the probability of the cauda equina syndrome in back pain patients without urinary retention is

approximately 1 in 10,000. The probability of cancer in patients presenting with back pain increases from approximately

0.7% to 9% in patients with a history of cancer (not including nonmelanoma skin cancer). In patients with any one of

three other risk factors (unexplained weight loss, failure to improve after 1 month, and age >50 years), the likelihood of

cancer only increases to approximately 1.2%.

Table 66–6 outlines some key recommendations with respect to the evaluation and management of low back pain. In the

absence of red flags, a conservative approach for at least 4 weeks is usually warranted, even if sciatica is present.

Magnetic resonance imaging is the preferred imaging procedure but can be reserved for the minority of patients with red

flags or persistent symptoms, especially neurological findings. The two most common indications for surgery are herniated

disc with persistent symptoms (especially radiculopathy) and spinal stenosis, which together account for less than 10% of

cases of chronic back pain. Recent trial data suggest that surgery may be only marginally beneficial for pain due to a

herniated disc but more helpful for spinal stenosis (Weinstein et al. 2006, 2008). Psychological factors are stronger

predictors of low back pain treatment outcomes than either physical examination findings or the severity or duration of

pain. Psychosocial factors that may predict poorer low back pain outcomes include presence of depression, passive coping

strategies, job dissatisfaction, higher disability levels, disputed compensation claims, and somatization.

TABLE 66–6. Key aspects of evaluation and management of low back pain

Most back pain (>70%–80%) improves in the first 2–6 weeks. Thus, a 4-week wait (i.e., a conservative approach) is warranted (even

with sciatica) in the absence of red flags.

Red flags that may prompt earlier diagnostic testing or referral include the following:

Cancer: history of cancer (strong predictor) or unexplained weight loss, failure to improve after 4 weeks, and age greater than 50

years (all weaker predictors)

Infection (vertebral): fever, intravenous drug use, recent infection (none well studied)

Compression fracture: older age, osteoporosis, steroid use

Cauda equina syndrome rare (0.04%); urinary retention 90% sensitive.

Physical examination focuses on a few cardinal neurological parts of the lower-body exam:

Straight-leg raising (SLR) in which the hip is flexed while the knee remains extended. Ipsilateral-positive SLR is 91% sensitive but

only 26% specific for radiculopathy, whereas a crossed-positive SLR (i.e., sciatica in the other leg) is only 29% sensitive but 88%

specific.

Lower-extremity motor and sensory exam:

Knee strength and reflexes (L4 nerve root); screen with squat and rise

Great toe and foot dorsiflexion strength (L5 nerve root); screen with heel walking

Foot plantar-flexion and ankle reflexes (S1 nerve root); screen with walking on toes

Diagnostic tests are needed in only a minority of cases (with red flags or persistent neurological signs).

MRI is the preferred imaging study (less radiation and better visualization of soft tissue, vertebral marrow, and the spinal canal).

With some weaker red flags (e.g., age >50 years), plain films and ESR may be obtained first and MRI obtained only if these tests

are abnormal or symptoms persist.Print: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Psychological factors are a stronger predictor of chronicity and functional outcomes such as disability than physical exam findings or

the severity or duration of pain.

Treatment: No treatment for back pain has good-quality (grade A) evidence of substantial benefit. The following have fair-quality

(grade B) evidence of moderate benefit or small benefits but no significant harm, costs, or burdens:

Pharmacotherapy: acetaminophen, NSAIDs, TCAs, tramadol/opiates, benzodiazepines

Nonpharmacological: chiropractic, acupuncture, massage, yoga, exercise, progressive relaxation, cognitive-behavioral therapy,

intensive interdisciplinary rehabilitation

Note. ESR = erythrocyte sedimentation rate; MRI = magnetic resonance imaging; NSAIDs = nonsteroidal anti-inflammatory drugs;

TCAs = tricyclic antidepressants.

Medications are the most frequently recommended intervention for low back pain. The most commonly prescribed

medications for low back pain are NSAIDs, skeletal muscle relaxants, and opioid analgesics (Chou and Huffman 2007a).

Benzodiazepines, systemic corticosteroids, antidepressant medications, and antiepileptic drugs are also prescribed.

Frequently used over-the-counter medications include acetaminophen, aspirin, and certain NSAIDs. No treatments for

back pain have grade A evidence supporting their use—that is, good-quality evidence of substantial benefits. Table 66–6

summarizes treatments with grade B evidence. For pharmacotherapy, this includes acetaminophen, NSAIDs, tramadol, and

TCAs. For all medications, the evidence of beneficial effects on functional outcomes is limited. Skeletal muscle relaxants,

which may be beneficial for acute back pain, do not have established efficacy for chronic pain. Although systematic

reviews of opioids for various chronic pain conditions have shown moderate benefits, the evidence for opioids specifically

for low back pain is sparse and inconclusive (Martell et al. 2007). A recent prospective study found that early prescription

of opioids for acute occupational low back injury was associated with an increased risk of work disability at 1 year, even

after adjustment for severity of pain, function, and initial injury (Franklin et al. 2008). A systematic review of 25 trials

involving 2,206 patients found no benefits for either continuous or intermittent traction in the treatment of low back pain

(Clarke et al. 2007). There is also good evidence that systemic corticosteroids are ineffective for low back pain with or

without sciatica. One systematic review identified only 7 trials evaluating medications for sciatica (Vroomen et al. 2000).

Two small trials suggest that gabapentin may be useful in the subset of patients with radiculopathy.

Ten trials were included in two systematic reviews of antidepressants (Salerno et al. 2002; Staiger et al. 2003). In all of

the trials, the duration of therapy ranged from 4 to 8 weeks. Antidepressants were consistently superior to placebo for

pain relief, whereas the benefits in terms of functional outcomes were uncertain. The pooled effect size for pain relief was

moderate (0.41). Indirect comparisons suggested modest benefits with TCAs but not with paroxetine or trazodone. A

recent review did not identify any relevant trials in back pain for SNRI antidepressants such as duloxetine or venlafaxine

(Chou and Huffman 2007a).

Osteoarthritis

Osteoarthritis is one of the most common musculoskeletal pain disorders (along with low back pain and fibromyalgia) in

both primary care and specialty settings. It typically increases with age (particularly after age 50), with the majority of

individuals older than 65 years having at least one joint affected by osteoarthritis. Common joints involve the distal and

proximal interphalangeal (but not metacarpal) joints of the fingers, the base of the thumb, the knees, the hips, and the

cervical and lumbar regions of the spine. The shoulder and elbow are rarely involved. The most common finding on

physical examination is an increase in joint size secondary to osteophyte formation. Plain radiographs are typically the

only diagnostic test required to confirm the diagnosis of osteoarthritis, which is manifested by loss of joint space and/or

osteophyte formation.

Unlike in rheumatoid arthritis and other inflammatory types of arthritis, the structural changes in osteoarthritis are not

amenable to specific disease-modifying treatments. Thus, the focus of treatment in osteoarthritis is reduction of pain and

preservation of function. Acetaminophen and NSAIDs, which are inexpensive and available without a prescription, are the

mainstays of pharmacotherapy. A systematic review of 13 trials in patients with osteoarthritis of the knee found that both

aerobic exercise and home-based quadriceps-strengthening exercise reduced pain (effect size, 0.52 and 0.39,

respectively) and disability (effect size, 0.46 and 0.32) (Roddy et al. 2005). Benefits of aerobic and strengthening

exercises in osteoarthritis patients were confirmed in a second systematic review (Brosseau et al. 2003). For advanced

disease with progressive pain and functional impairment, total hip arthroplasty and knee arthroplasty are effective. In

contrast, a systematic review of 23 studies found inconclusive evidence for the benefits of arthroscopic lavage and/or

debridement in knee osteoarthritis (Samson et al. 2007). Glucosamine, chondroitin, and intra-articular hyaluronic acid

have been the most popular CAM treatments for osteoarthritis, but 4 systematic reviews as well as an overall review

(Table 66–7) found that the evidence regarding the efficacy of each of these three treatments is still inconclusive (Arrich

et al. 2005; Distler and Anguelouch 2006; Reichenbach et al. 2007; Samson et al. 2007; Vlad et al. 2007).

TABLE 66–7. Glucosamine, chondroitin, and hyaluronic acid for osteoarthritis (OA): summary of systematic reviews

Treatment Study Condition Review type Benefits Strength

of

evidence

Comments

Glucosamine Vlad et al.

2007

Knee or

Hip OA

Meta-analysis (15

trials, 2,825

Not

known

Moderate Glucosamine hydrochloride (three trials) did

not have a significant effect size (0.06), butPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Treatment Study Condition Review type Benefits Strength

of

evidence

Comments

patients)

glucosamine sulfate (12 trials) did (0.44).

However, large heterogeneity among trials

made conclusions about efficacy uncertain.

Chondroitin Reichenbach

et al. 2007

Knee or

Hip OA

Meta-analysis (20

trials, 3,846

patients)

No Moderate Minimal to no effect on symptoms. Only

three large high-quality trials, which

accounted for 40% of patients.

Glucosamine

and/or

chondroitin

Distler and

Anguelouch

2006

Knee or

Hip OA

Review of prior

reviews

No Moderate Review of four prior meta-analyses and

large GAIT trial concluded that neither

glucosamine nor chondroitin is effective in

1.  

Glucosamine

and/or

chondroitin

Samson et al.

2007

Knee OA Systematic (21

trials)

Not

known

Moderate Evidence from small trials inconclusive. The

GAIT study in 1,583 patients showed no

difference from placebo.

Hyaluronic acid

(intra-articular)

Arrich et al.

2005

Knee OA Meta-analysis (22

trials)

No Moderate Small but clinically insignificant effect on

pain. Only four high-quality trials.

Hyaluronic acid

(intra-articular)

Samson et al.

2007

Knee OA Systematic (42

trials)

Not

known

Moderate Generally some modest benefits compared

with placebo but unclear clinical

significance.

Note. GAIT = Glucosamine–Chondroitin Arthritis Intervention Trial.

Avouac et al. (2007) conducted a meta-analysis of trials evaluating opioid therapy in osteoarthritis patients. Of the 18

placebo-controlled trials, 13 assessed pain intensity for 2,438 participants receiving opioids and 1,295 receiving placebo.

Six studies evaluated stronger opioids (oxycodone in 4 studies, fentanyl and morphine in 1 study each) and 7 studies

examined weaker opioids (tramadol in 4 studies, tramadol–acetaminophen combination in 2 studies, and codeine in 1

study). The median trial duration was 12 weeks. The pooled effect size for pain intensity was moderate, at –0.79 (95% CI

= –0.98 to –0.59). Sensitivity analysis showed no changes in the conclusions by type of opioid studied, type of scale used

to assess pain, or methodological quality of the study. Physical function was assessed in 5 trials, with 1,429 participants

receiving opioids (tramadol–acetaminophen in 2 studies; morphine, tramadol, and codeine in 1 study each) and 595

receiving placebo. The median trial duration was 4 weeks. The pooled effect size for physical function was small, at –0.31

(95% CI = –0.39 to –0.24). Again, sensitivity analyses did not change the conclusions. The average treatment

discontinuation rate for toxicity was 25% in the opioid group (31% for strong opioids and 19% for weak opioids) versus

7% in the placebo group.

Unlike the many trials of antidepressants for neuropathic pain, fibromyalgia, and chronic low back pain, antidepressants

have not been well studied as a treatment for the pain of osteoarthritis. However, recent studies have shown that when

depression co-occurs with arthritis, it can explain as much of the variance in pain intensity as objective severity of the

arthritis (Katon et al. 2007). Also, RCTs have shown that treatment of depression in arthritis patients may reduce pain as

well as depression (Bair et al. 2008; E. H. Lin et al. 2003). Thus, while antidepressants cannot currently be recommended

in osteoarthritis patients without depression, screening for and comanaging depression may benefit patients in their pain

outcomes.

ALGORITHMIC APPROACH TO TREATMENT OF CHRONIC PAIN

This chapter focuses on the main classes of treatments for chronic pain, with a particular emphasis on pharmacotherapy

but also briefer synopses of nonpharmacological treatments. Four of the most common disorders in which pain is a

predominant treatment target are discussed: neuropathic pain, fibromyalgia, low back pain, and osteoarthritis. Acute pain

and cancer pain are not specifically addressed, nor are two other common sources of chronic pain—headache and regional

pain syndromes—reviewed. Based on our reviews within these parameters, an evidence-based algorithm for treating pain

is summarized in Figure 66–1.

FIGURE 66–1. Analgesic algorithm for chronic pain.Print: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Algorithm for an evidence-based approach to treatment selection in the management of chronic pain. Nonpharmacological treatments

can be considered at any step; ones that have proven effective in several types of pain conditions include exercise,

cognitive-behavioral therapy, pain self-management, and acupuncture. CrCl = creatinine clearance; FDA = U.S. Food and Drug

Administration; max = maximum; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin–norepinephrine reuptake inhibitor;

SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCAs = tricyclic antidepressants.

OTHER ISSUES

Treatment of Pain Comorbid With Depression or Anxiety

As mentioned earlier, there is substantial evidence for a pain-depression dyad and probably a pain–depression–anxiety

triad (see “Psychiatric Comorbidity”). The comorbidity among these disorders ranges from 30% to 60%, and they have

reciprocal adverse effects on quality of life, disability, health care use, and treatment response. In particular, the presence

of pain negatively affects depression outcomes, while depression in turn makes pain treatments less effective. Anxiety

may have a similar effect, although the research in this area is less substantial than for depression.

Several trials have shown that depression treatment also benefits patients in pain outcomes, although the effect size for

pain is only about half that for depression (Bair et al. 2008; Greco et al. 2004; E. H. Lin et al. 2003). Until more trials are

conducted in those with depression and comorbid pain, several suggestions may be considered. First, pain should be asked

about when treating depressed or anxious patients, particularly in those who are not achieving remission or optimal

responses. Likewise, psychiatric screening should be considered in patients with persistent pain, possibly with brief

measures that screen for both depression and anxiety (Kroenke et al., in press). Second, it may be that antidepressantPrint: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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selection is important when pain is a major problem. For some types of pain conditions, TCAs and SNRI antidepressants

appear to be more effective than SSRI or other antidepressants, although head-to-head trials are still few. Third, adding

CBT, PSM (pain self-management) programs, or other nonpharmacological treatments proven effective for pain could be

considered. Fourth, optimizing analgesic management in patients with depression and pain, rather than simply focusing on

depression medications, may be important. Increasingly, we may need to consider pain and depression as dual diagnoses,

where attention to both is necessary to optimize patients’ outcomes.

Placebo Effect

As with other symptom-based conditions (e.g., depression, anxiety, somatoform disorders), pain has a placebo response in

the 30%–40% range or higher. This can make it challenging to separate the specific effects of a pain

treatment—medication or nonpharmacological—from placebo or other nonspecific effects. Furthermore, it means that the

more successful a trial is in masking the patient to active versus control treatment (typically greatest in a

placebo-controlled drug trial), the lower the estimated differences from placebo are likely to be. In contrast, less effective

masking (e.g., attention–placebo control groups for psychotherapy or behavioral interventions, sham procedures for

acupuncture or chiropractic manipulation) or nonexistent masking (e.g., wait-list or treatment-as-usual control groups)

are more likely to overestimate the effect of a pain treatment.

At the same time, the role of placebo effects on pain outcomes can be useful in clinical practice, including patient

expectancy for an analgesic outcome and the clinical benefits of a positive therapeutic relationship. Pain is the most

frequent reason for seeking CAM care (Astin 1998). Although evidence for several CAM treatments may still be lacking,

their placebo effects coupled with frustration among many allopathic physicians and patients in the context of chronic pain

may account for the popularity of CAM treatments for pain.

Experimental work has also revealed some interesting physiological effects of placebo. A meta-analysis of 12 studies

(1,183 participants) was conducted to examine the effects of placebo and an opioid antagonist, naloxone, on pain (Sauro

and Greenberg 2005). Placebo administration was associated with a decrease in self-reported pain, and a hidden or blind

injection of naloxone reversed placebo-induced analgesia. A recent experimental study in 20 healthy subjects found that

the placebo and nocebo effects (i.e., the therapeutic and adverse effects, respectively, of inert substances or sham

procedures) are associated with opposite responses of dopaminergic and endogenous opioid neurotransmission in a

distributed network of regions throughout the brain (Scott et al. 2008). The results support other literature showing that

the belief in and expectation of analgesia induce discrete physiological changes, leading to relief from pain, and this

response may be mediated by endogenous opioids.

Assessment and Monitoring of Pain

Clinical trials have often used a wide variety of pain measures in assessing outcomes, and until recently, consensus has

been lacking on a standard or optimal approach. This is not unlike other psychiatric disorders or symptom-based

conditions where patient-reported measures are necessary to assess clinical outcomes, in contrast to disorders where a

universally agreed-on physical measure (e.g., blood pressure) or laboratory test (e.g., for serum cholesterol levels) is the

criterion standard. In a review of pain clinical trials published in seven top-tier medical journals in 2003, a total of 50

studies used 28 types of pain assessments (Litcher-Kelly et al. 2007). The most frequently used assessments were a

single-item visual analog scale and a single-item 0–10 numeric rating scale (NRS); multidimensional inventories were

used infrequently.

Inadequate pain assessment has been identified as a key barrier to appropriate pain management. Important initiatives

have aimed to increase awareness of pain as a clinical problem by promoting better pain assessment. The U.S. Department

of Veterans Affairs (VA) campaign promoting “pain as the fifth vital sign” requires all VA facilities to assess patients using

an NRS of 0–10 for current pain. Even more far-reaching, the Joint Commission on Accreditation of Healthcare

Organizations (2000) pain assessment and management standards, implemented in 2001, require accredited health care

facilities to assess all patients for pain in both inpatient and ambulatory care settings. Although Joint Commission

standards do not mandate a specific method of pain assessment, many organizations have responded by adopting use of

an NRS of pain as the “fifth vital sign” (Dahl 2002). A verbal (interviewer-administered) and visual (self-rated) version of

this single-item NRS for pain assessment is shown in Figure 66–2. As a result, assessment of current pain intensity with a

single-item rating scale has become nearly ubiquitous in many U.S. health care settings. However, this movement has not

led to clear improvements in the quality or outcomes of chronic pain management, and studies have shown that the NRS

may not be the optimal measure for assessing and monitoring chronic pain in clinical practice (Krebs et al. 2007; Mularski

et al. 2006). An important limitation of single-item pain measurement is that it provides an overly simplified picture of a

complex subjective experience.

FIGURE 66–2. Pain numeric rating scale (NRS).Print: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Interviewer-administered (verbal) and self-administered (visual) versions of the single-item NRS for pain, also referred to “the fifth

vital sign.”

Recent consensus recommendations from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials

(IMMPACT) recommend four core chronic pain outcome domains for monitoring treatment response: pain intensity (i.e.,

severity), physical functioning (i.e., pain-specific disability), emotional functioning (largely depression), and patient-rated

overall improvement (Dworkin et al. 2008). The first two domains are captured in the recently validated PEG pain scale

based on three items from the Brief Pain Inventory (average pain severity, interference with enjoyment of life, and

interference with general activities), shown in Figure 66–3 (Krebs et al. 2008a). For emotional functioning, a clinical or

patient-rated assessment of depression is recommended. For overall improvement, the single-item Patient Global

Impression of Change scale uses a seven-point rating scale with the options “very much improved,” “much improved,”

“minimally improved,” “no change,” “minimally worse,” “much worse,” and “very much worse.”

FIGURE 66–3. PEG three-item pain scale.

The PEG three-item pain scale—an ultrabrief measure for assessing and monitoring pain—is based on three items from the Brief Pain

Inventory: average Pain severity, interference with Enjoyment of life, and interference with General activities.

Source. Krebs EE, Bair MJ, Damush TM, Sutherland JM. Used with the authors’ permission.

The competing demands of clinical practice in which visits are short and pain is often a secondary focus make efficiency as

well as validity of assessment a paramount concern. At the same time, there must be a balance between number of items

and key operating characteristics such as reliability, validity, and responsiveness to therapy. For example, “ultrabrief”

depression measures containing two or three items perform better than single-item depression measures (Mitchell and

Coyne 2007). In this sense, the three-item PEG may be preferable to the single item NRS, which is currently promulgated

by various accrediting bodies but which has substantial limitations, as demonstrated in two recent studies (Krebs et al.

2007; Mularski et al. 2006). Moreover, the PEG captures both the severity and the functional interference dimensions of

pain, whereas the NRS captures only pain severity. This is essential in pain management because pain interference has

been shown to have an even greater impact than simple severity on quality of life and other patient-centered outcomes

(Von Korff et al. 1992).Print: Chapter 66. Treatment of Chronic Pain Syndromes http://www.psychiatryonline.com/popup.aspx?aID=438953&print=yes…

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Economic Issues

As mentioned in the introduction to this chapter, pain costs the United States more than $100 billion each year in health

care and lost productivity (Stewart et al. 2003), and pain medications are the second most prescribed class of drugs (Turk

2002). Despite the importance of considering drug costs, a recent review of 142 chronic pain–related economic

evaluations published between 1988 and 2006 found important methodological shortcomings (Vetter 2007). Only a few

studies combined the economic analysis along with an RCT, the economic endpoints had limited time horizons, and there

was a failure to address the protracted costs versus benefits of treating long-term and often recurrent chronic pain

conditions. Unlike many cardiology and oncology trial–based economic evaluations with societal perspectives and

protracted time horizons (e.g., longer-term survival or death), many of the economic analyses related to chronic pain

treatment have been restricted to a third-party insurer perspective and have used a limited time horizon of less than 1

year. For example, it is possible that a more expensive medication may be more cost-effective than a lower-cost

medication if it were shown that time lost from work was less or enhancements in quality in life were greater. In an

economic evaluation of controlled-release oxycodone compared with oxycodone–acetaminophen for osteoarthritis, the

more costly controlled-release medication proved more effective and less costly from a societal perspective, including

greater gains in quality-adjusted life years and lower costs associated with time lost from work or other activities

(Marshall et al. 2006). In a similar evaluation of pregabalin versus gabapentin for neuropathic pain, the authors concluded

that pregabalin was more cost-effective, costing about $15 for each additional day with no pain or only mild pain and

about $600 for each additional patient with no pain or mild pain (Rodríguez et al. 2007). Both studies used simulated

analyses from existing trial data rather than head-to-head comparisons in an RCT, so the conclusions must be interpreted

with caution. Nonetheless, pharmacoeconomic decision making needs to incorporate not only drug costs but also

differential efficacy and side effects, impacts on work and quality of life, and the adjudication of patient, insurer,

employer, and societal perspectives.

Gaps in Knowledge Base Regarding Treatment of Chronic Pain

There are several important gaps in our knowledge regarding treatment that in fact are probably not unique to chronic

pain. First, there is a paucity of head-to-head trials, meaning that although we can draw conclusions about the

effectiveness of a particular monotherapy compared with a placebo or minimal treatment, we have much less information

about the comparative effectiveness of different treatments. Second, few trials have evaluated different strategies for

choosing initial treatment, so that deciding between first-line and subsequent treatments is more a matter of expert

consensus, clinician experience, and patient preferences. Third, evidence is sparse on the effectiveness of dual-medication

or other combination therapy versus monotherapy or sequential treatment, even though patients are frequently prescribed

more than one medication or treatment. Fourth, most treatment trials have been short-term, so evidence of benefits

sustained beyond 4–12 weeks is often lacking; this is a critical gap given the fact that our focus is on the management of

chronic pain.

Despite these gaps, substantial evidence has accumulated over the past several decades about what works and what does

not work for treating chronic pain. Avoiding ineffective treatments and maximizing the use of treatments proven beneficial

in clinical trials are likely to produce better outcomes than have often been experienced by clinicians and patients in the

management of chronic pain.

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