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Pharmacologic Pain Treatment of Musculoskeletal Disorders: Current Perspectives and Future Prospects

Curatolo, Michele M.D., Ph.D.; Bogduk, Nikolai M.D., Ph.D., D.SC.

The Clinical Journal of Pain: March 2001 - Volume 17 - Issue 1 - p 25-32
Special Topic Series: Musculoskeletal Pain
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Objective: The authors aimed to provide an educational update on the current evidence of the effectiveness of drug therapy in the treatment of musculoskeletal pain and to offer a perspective of possible future developments.

Design: The authors used a pragmatic review of data provided by available systematic reviews and seminal controlled studies pertaining to the treatment of regional musculoskeletal pain problems.

Results: Epidural steroids may offer limited, short-term benefit for sciatica. Local injections of steroids are either ineffective or provide short-lasting benefits. Nonsteroidal anti-inflammatory drugs and opioids reduce pain, but the effect size is modest. The literature does not support convincingly the use of antidepressants. Certain muscle relaxants may be useful in the treatment of back pain. Hyaluronic acid, neutraceutical agents, avocado-soybean unsaponifiable agents, oxaceprol and diacerein may be effective in the treatment of osteoarthritis, but the information regarding these new agents does not allow wholesale endorsement of these substances. Selective epidural injection of steroids at a target nerve root approached through the intervertebral foramin has the potential to replace the traditional epidural approach. Long-acting, C-fiber-specific local anesthetics are under investigation and could provide long-lasting pain relief without motor or sensory impairment. In the future, central hypersensitivity in chronic musculoskeletal pain might be treated using antagonists of the N-methyl-D-aspartate receptor. Cannabinoid agents produce antinociception and prevent experimentally induced hyperalgesia in animals, and they may find a role in pain management. Methods to optimize drug combinations are available.

Conclusions: The effectiveness of the currently available drugs in the treatment of musculoskeletal pain conditions is disappointing. Recent developments may open new perspectives in this area of pain medicine.

*Department of Anesthesiology, Division of Pain Therapy, University Hospital of Bern, Bern, Switzerland, and †Bone and Joint Institute, University of Newcastle, Newcastle, Australia

Address correspondence and reprint requests to Dr. Michele Curatolo, Department of Anesthesiology, Division of Pain Therapy, Inselspital, 3010 Bern, Switzerland; e-mail: michele.curatolo@insel.ch

Both the acute and the long-term phases of musculoskeletal pain constitute a significant health problem in Western countries.1-3 The condition is common in primary care settings, and it probably accounts for the majority of patients seen in pain clinics, usually in the form of back pain and neck pain. Typically, however, a pathoanatomic diagnosis of the cause of pain cannot be made. The source of pain usually cannot be established using conventional means. For this reason, most musculoskeletal pain conditions are labeled anatomically as regional pain syndromes, such as back pain and neck pain. For shoulder pain, there are many traditional diagnostic labels, such as supraspinatus tendinitis, frozen shoulder, subacromial bursitis, among other, but contemporary research has shown that traditional diagnostic tests for these conditions lack reliability, validity, or both.4-6 Therefore, even shoulder pain becomes a regional musculoskeletal condition. Knee pain may result from injuries to the menisci or other intra-articular structures, but in the absence of trauma the cause of knee pain is elusive. Conventionally, regional knee pain has been attributed to osteoarthritis, but the validity of this premise has been questioned recently.7,8

In the absence of a pathoanatomic diagnosis and other effective therapies, musculoskeletal pain commonly is treated using drugs. Drug therapy for musculoskeletal pain, however, is changing. Controlled trials and systematic reviews have addressed the effectiveness of commonly used drugs for common musculoskeletal pain conditions. The results are sobering, if not disconcerting. Conversely, new drug therapies that promise alternative means of treating these conditions are being explored and developed. The purpose of this review is to provide an educational update regarding this change.

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METHODS

The current review is composed deliberately to be a classic, pragmatic review. Its purpose is to be educational. It makes no pretense of being a systematic or blind review. Instead, it draws on the results of published systematic reviews and articles regarding topics that have not attracted systematic reviews. Reviews and articles were drawn from the personal libraries of the authors, which were developed through systematic searches of the literature during studies of various treatments of regional musculoskeletal pain problems. Those searches used electronic databases, such as MEDLINE, EM-Base, and the Cochrane Collaboration and bibliographies of publications regarding musculoskeletal pain that were held or were retrieved by the authors. The focus of the searches was musculoskeletal pain and its treatment. The pharmacology and pharmaceutical literature was not searched deliberately. Consequently, this review does not pretend to be comprehensive about every aspect of any drug that might be used for musculoskeletal pain. As an educational article, it consciously focuses on the musculoskeletal literature to highlight cardinal reflections, trends, and future developments.

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CONVENTIONAL THERAPIES

Musculoskeletal pain has been treated using a variety of agents administered in a variety of ways. Analgesics, both simple and opioid, and nonsteroidal anti-inflammatory agents (NSAIDs) administered orally are the most commonly used drugs. Less commonly, corticosteroids have been administered via injection into joints, around tendons or other painful structures, and into the epidural space. Local anesthetics have been administered in a similar manner to similar sites, often in conjunction with corticosteroids.

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Lumbar and caudal epidural injection of steroids

A systematic review of the effectiveness of epidural steroids in the treatment of low back pain associated with radiculopathy showed the poor quality of literature and concluded that there was insufficient evidence to support their use.9 In contrast, a meta-analysis concluded that a pooled effect size favored use of epidural steroids,10 although the number needed to treat was high.11 That study,10 however, warned that meta-analysis was not a substitute for the results of a properly designed randomized controlled trial. That trial soon followed and compared the effects of a lumbar epidural injection of steroids with a similar injection of normal saline.12 A statistically significant short-term reduction of leg pain in the patients treated with steroids was shown, but no significant difference between the two groups regarding functional outcome, return to work, or social disability was shown. After follow-ups at 3 months and 12 months, no difference was found between the groups in any variable.

Older studies13-15 purported to show that using a local anesthetic plus a steroid was superior to using a local anesthetic alone, when injected caudally, but they provided insufficient data to allow critical evaluation of this claim. One study found no difference in outcome between patients treated using procaine with methylprednisolone or using only procaine.16 More recent studies17,18 showed effects in favor of steroids, but each study was small and lacked sufficient statistical power to be absolutely convincing. The effects of caudal epidural steroids are no more than temporary. Benefits are evident immediately and at 4 weeks decrease rapidly. Few patients sustain enduring relief greater that attributable to natural history.17,19

The published literature questions the effectiveness of lumbar epidural steroids, but considers caudal epidural steroids to be a potentially useful option in the treatment of lumbar radicular pain. However, caudal epidural steroids are not curative, and they constitute a temporary measure to relieve pain while natural resolution occurs, or perhaps to provide a window of opportunity for multimodal rehabilitation programs.

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Local injection of steroids

Injections of corticosteroids have been used for a variety of musculoskeletal pain problems believed to arise from structures or tissues within joints, around joints, or in tendons. Steroids have been used, ostensibly for their anti-inflammatory effect, but, paradoxically, this belief contradicts the lack of evidence that inflammation is involved in the conditions treated. This contradiction is substantiated by their lack of effectiveness.

For epicondylitis of the elbow, two systematic reviews20,21 found that using steroid injection was marginally superior to saline injection or lidocaine injection alone, but the quality of the literature was poor. Another review22 captured some earlier literature and a more recent study.23 It found that the pooled odds ratio for benefit at less than 6 weeks was 0.15 (CI = 95%; range = 0.10-0.23). Beyond 6 weeks, no statistically significant benefit was shown.

In the treatment of shoulder pain, two systematic reviews found little evidence to support the effectiveness of corticosteroid injections.24,25 Adding steroids to lidocaine does not provide an additional benefit in the treatment of rotator cuff tendinitis.26 Methylprednisolone combined with lidocaine is no more effective than using normal saline in the treatment of supraspinatus tendonitis.27 In the treatment of frozen shoulder, steroids are no more effective than local anesthetics alone.28 However, administration by injection is superior to physiotherapy in the treatment of shoulder pain.29

Although anecdotal evidence supports intra-articular injections of corticosteroids for osteoarthritis of the knee,30 controlled trials are lacking. In the treatment of zygapophysial joint pain, intra-articular steroids have proven to be no more effective than local anesthetic alone in the treatment of neck pain31 and they are no more effective than intra-articular normal saline in the treatment of low back pain.32 In summary, the literature casts doubt on the effectiveness of local injections of steroids. Depending on the condition, effects are nil or minimal, and the data do not show long-term benefits.

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Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs are probably the mainstay of drug treatment of acute and chronic musculoskeletal pain problems. Although they may be a legitimate temporary measure in the treatment of short-term episodes of acute pain or while a patient with chronic pain awaits a more definitive treatment, such as a joint replacement, the evidence does not support NSAID use as long-term or solo therapy.

In the treatment of epicondylitis of the elbow, diclofenac is better than placebo in providing pain relief, but it does not produce functional improvement and side-effects are common.33 Topical NSAIDs do not provide a greater benefit than strapping or manipulation.34 In the treatment of shoulder pain, a systematic review of the effectiveness of NSAIDs found that the quality of most trials was "disappointing."35 The three trials with the highest scores for methodology showed evidence of short-term effectiveness of NSAIDs, but those effects were not sustained in the highest scoring trial.36

There are no systematic reviews of the use of oral NSAIDs in the treatment of knee pain, but several studies have tested the effectiveness oral NSAIDs in the treatment of a variety of knee conditions. In the treatment of osteoarthritis, paracetamol is superior to placebo, and it is comparable in terms of effectiveness to ibuprofen and naproxen.37,38 In the treatment of chondromalacia patellae, aspirin provides no greater benefit than that of placebo.39 Topically applied NSAIDs in the treatment of musculoskeletal disorders, including knee pain, seem to be superior to placebo, but the effect is modest, with only one patient in three benefiting.40

In the treatment of neck pain, the literature on drug therapy is sparse. The Quebec Task Force on Whiplash Associated Disorders found no studies of the benefit of analgesics in the treatment of pain after whiplash injury.41 A review of conservative therapy for neck pain42 identified one study that reported that using the combination of a topical anti-inflammatory agent and transcutaneous electrical stimulation (TENS) was superior to using only TENS,43 but the effect size could not be calculated.42 The review also identified a thesis that compared drug therapy and education with placebo and found no difference in outcome, but it commented that the sample size was too small to exclude a difference.

A systematic review of the treatment of low back pain using NSAIDs44 found that the literature suggested that NSAIDs are effective for short-term symptomatic relief. However, NSAIDs are less effective or ineffective in patients with back pain associated with radicular pain. No long-term data were available. Nonsteroidal anti-inflammatory drugs were equal or slightly superior to paracetamol or dextropropoxyphene. Another systematic review from the same group45 provided these same conclusions.

The recent introduction of inhibitors of the cyclooxygenase-2 enzyme (COX-2) may improve the side-effect profile of NSAIDs. In a study comparing celecobix, a COX-2 inhibitor, with diclofenac, a nonspecific COX-2 inhibitor, in the treatment of rheumatoid arthritis, the incidence of gastroduodenal ulcer detected endoscopically and the rate of withdrawal for gastrointestinal adverse effects was significantly less in the celecobix group.46 However, celecobix was not better than diclofenac in relief of pain, and the quantitative effect was minimal, amounting to a 6.6-mm reduction on a 100-mm visual analog scale for pain after 24 weeks. A study of osteoarthritis that compared celecobix, naproxen (a non-specific COX-2), and placebo found the effectiveness of celecobix to be superior to placebo but comparable to that of naproxen.47 On average, a reduction of more than 30% in pain severity was observed. However, the long-term effectiveness and safety of COX-2 enzyme inhibitors are unknown.48

Nonsteroidal anti-inflammatory drugs have limited effectiveness in the treatment of musculoskeletal pain. The published evidence does not support the extensive use of NSAIDs in the treatment of musculoskeletal pain.

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Opioids

Opioids are increasingly used in the treatment of chronic noncancer pain. The main rationale is the reappraisal of probably overestimated problems attributed to opioids, such as risk of addiction or tolerance.49 However, there are almost no controlled trials regarding their effectiveness in the treatment of musculoskeletal pain, and none that show unequivocal benefits. One trial found oral morphine to be superior to active placebo in relieving chronic regional musculoskeletal pain, but pain relief was quantitatively modest and not associated with functional or psychological improvements.50 Another trial found that in patients with chronic back pain, opioids achieved only minor reductions in pain, without an effect on activity and without long-term benefits.51 Therefore, the use of opioids in the treatment of chronic nonmalignant pain is not supported by evidence of effectiveness and safety. Opioids may be useful, but they do not constitute major progress in the treatment of musculoskeletal pain.

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Antidepressants

A systematic review52 found the literature on antidepressants and low back pain to be poor and not compelling in support of their use. One study53 indicated a superiority of imipramine over placebo, but only in regard to "number of days had to lie down" and "number of days with at least some restriction of normal activity"; no differences were shown with regard to pain intensity, depression, feeling miserable, overall evaluation of symptoms, and physical findings. Another study54 showed amitriptyline to be superior to placebo, but only with regard to use of analgesics. Trazodone55 and imipramine56 did not show superiority to placebo. Two controlled studies found nortriptyline and maprotiline (but not paroxetine) to be superior to placebo in the treatment of low back pain,57,58 but the effect was modest: nortriptyline reduced pain intensity by 22% (in comparison with a reduction of 9% using placebo) and maprotiline by 45% (in comparison with a reduction of 27% using placebo). Reduction in disability minimally favored nortriptyline over placebo, but health-related quality of life and mood did not differ between treatments.

The available literature does not convincingly support the use of antidepressants in the treatment of chronic musculoskeletal pain. Physicians should consider whether achieving little more than a placebo effect justifies patients having to endure the side effects of these drugs.

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Other agents

In a review of conservative therapy in the treatment of neck pain,42 two investigations of the use of muscle relaxants were identified.59,60 In those studies, muscle relaxants were said to be effective in patients with pain associated with muscle spasm, but the effect size could not be calculated.42 A systematic review found strong evidence that certain muscle relaxants are superior to placebo in the treatment of acute low back pain, but little evidence for their effectiveness in the treatment of chronic low back pain.45

Injections of hyaluronic acid have been explored as a means of treating osteoarthritis of the knee. Replacement of a critical constituent of synovial fluid in a desiccated joint is the rationale for such a procedure. A pragmatic review, however, found insufficient unequivocal evidence of effectiveness, but found that intra-articular hyaluronan probably could be considered as an option for patients in whom other drug treatment was ineffective and for whom surgery was not an option.61

Neutraceutical agents are a new-age option in the treatment of osteoarthritis of the hip or knee. They involve the ingestion of components of cartilage, ostensibly to promote or to facilitate cartilage reformation. The particular agents used are glucosamine and chondroitin, which are used more as nutritional supplements than as conventional "drugs." Reviews of early studies show a superiority to placebo but problems exist regarding the rigor of the studies and the consistency of the preparations used.62

Avocado-soybean unsaponifiable agents are made of unsaponifiable fractions of one third avocado oil and two thirds soybean oil. They inhibit the deleterious effects of different mediators on joint structures and have been found to be superior to placebo in patients with osteoarthritis of the hip or knee.63

Oxaceprol is an amino-acid derivative that inhibits leukocyte adhesion, and migration.64 This drug is as effective as and tolerated better than diclofenac in the treatment of osteoarthritis of the hip and knee.65

Diacerein has been used in the treatment of osteoarthritis. Its metabolite rhein66 inhibits interleukin-1 activity, reduces collagenase production in the articular cartilage, and inhibits superoxide anion production, chemotaxis, and phagocytic activity of neutrophils; and macrophage migration and phagocytosis.67 Its effectiveness is similar to that of NSAIDs, but it has a slower onset of action.67

These various drugs, particularly the avant-garde agents, offer promise of new options in the treatment of osteoarthritis pain. However, the literature does not allow an endorsement of their effectiveness in the treatment of musculoskeletal pain.

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NEW PERSPECTIVES

Transforaminal steroids

One reason that conventional epidural steroids fail to show effectiveness in the treatment of radicular pain could be that the injected drug fails to reach the targeted tissue in sufficient quantity. This limitation has been overcome by the development of transforaminal injections. In this procedure, a needle is directed under fluoroscopic control onto the affected spinal nerve. A preliminary injection of contrast medium ensures that the target nerve is adequately bathed by the injectant and that the injectant has avoided the intrathecal space. Subsequently, the needle is used to administer corticosteroids directly to the affected nerve.

Two uncontrolled studies using this procedure for lumbar radiculopathy secondary to disc herniation reported high effectivness for pain and disability during long-term follow-up.68,69 In a prospective, controlled, double-blind study,70 patients with nerve root compression who were scheduled for surgery, were randomized to receive bupivacaine alone (n = 27) or bupivacaine with betamethasone (n = 28). Nine patients in the bupivacaine group and 20 patients in the bupivacaine-betamethasone group elected not to undergo surgery. The difference was statistically significant. These data suggest that transforaminal steroid injection could become an attractive option for patients otherwise destined for surgical treatment of sciatica. Given its greater effectiveness and more enduring effects, this procedure has the potential to replace the traditional epidural approach for the treatment of lumbar radicular pain.

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Local anesthetics

Local anesthetics stop pain. When injected accurately into the proper nerve, they produce immediate and complete relief of pain, which no other drug does as consistently.

One factor that limits the usefulness of local anesthetics as analgesics is their relatively short duration of action, which has prompted the development of means by which to extend and prolong the action of local anesthetic agents. The encapsulation of local anesthetic agents into liposomes71 or into slowly biodegradable polymers72 is being investigated.

An additional problem with local anesthesia is the concomitant block of sensory and motor fibers. Sodium channel blockers selective for C fibers are being developed.73 These agents offer the promise of providing pain relief without the attendant numbness or motor impairment that occur with conventional local anesthetic agents.

The perfection of ultra-long-acting C-fiber selective-local anesthetic agents could revolutionize musculoskeletal pain medicine. The profound relief that they offer would more than compensate for the need for repeated injection. For joint pain, highly selective, long-acting agents could make surgery obsolete.

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Antagonists of the N-methyl-D-aspartate (NMDA) receptor

Psychophysical studies have shown that patients with chronic musculoskeletal pain have hyperalgesia that occurs not only locally, but also in sites away from the painful area.74-76 The widespread distribution of hyperalgesia indicates alterations in the central processing of nociceptive input. Experimental studies have shown that central hyperalgesia may result from maintenance of central hypersensitivity by an ongoing peripheral nociceptive input,77 persistence of central sensitization after resolution of a primary peripheral event,78 or imbalance of the descending modulator system.79

The extent to which central hypersensitivity contributes to the total pain experience of patients with musculoskeletal pain is unclear, but the possibility of selectively treating central hypersensitivity is interesting. The hyperalgesia associated with central hypersensitivity can be blocked by NMDA antagonists,80 and the development of potent, well-tolerated NMDA antagonists may provide new perspectives in the treatment of musculoskeletal pain.

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Cannabinoids

Cannabis has been used as a medicinal plant for thousands of years for a variety of illnesses, including pain syndromes. Cannabinoids are being investigated extensively. In animal studies, they reverse inflammation-induced allodynia81; they block the development of experimental hyperalgesia82; and they enhance morphine-induced antinociception.83 Interestingly, cannabinoids are antiemetic, whereas nausea is a frequent problem during opioid therapy.

If these findings are confirmed in humans, cannabinoids may play a role in pain management, alone or in combination with other analgesics. To date, these drugs are still on the list of forbidden substances in most countries.

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Drug combinations

An attractive idea is the use of combinations of drugs to treat pain. Combinations may reduce the dosage required of individual drugs and, thus, the side-effects of each, without reducing the total potency. With some combinations the potency might be facilitative rather than additive. However, determining the optimal combination is a problem. If addressing systematically, rather than by trial and error, the mathematics is daunting. For example, if three drugs and four doses for each drug are considered, 64 (43 = 64) different combinations exist. Clearly, an investigation performed for such a high number of combinations is not feasible. Therefore, the optimal combination is unlikely to be identified using randomized controlled studies because only a small proportion of all possible combinations could be analyzed.

Recently, an optimization model84 was applied for the first time to a clinical investigation85 to optimize postoperative epidural analgesia. Initially, a few combinations were chosen empirically and evaluated. On the basis of the results obtained, new combinations were created stepwise and investigated. The concept was to use the information obtained at each step to move toward the optimal combination. In this way, the optimum can be identified by testing a small number of combinations.86

This example paves the way for the systematic exploration of drug combinations for other pain conditions and for other drugs. A systematic approach offers the prospect of rationalizing what seems to be haphazard, undisciplined use of drugs for musculoskeletal pain.

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CONCLUSIONS

The effectiveness of the drugs used in musculoskeletal pain conditions is disappointing. Many are ineffective. Others are successful in reducing the level of pain, but the effect is modest or lasts briefly. The effect of drugs on disability and quality of life is nil or minimal. It seems that prescribing drugs satisfies a humanitarian urge by offering some degree of pain relief. This may be a valuable achievement in the context of daily pain, but if complete resolution of pain and disability is the aim of treatment, we must admit that there is no pharmacologic therapy by which these goals can be reached. Recent developments offer new perspectives regarding the pharmacologic treatment of musculoskeletal pain that may provide a better means of satisfactory pain management.

Acknowledgments: Supported in part by the National Musculoskeletal Medicine Initiative, initiated by the Australian Federal Minister for Health and sponsored by the Commonwealth Department of Health and Human Resources, and by the Department of Anesthesiology of the University of Bern, Bern, Switzerland.

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Keywords:

Drug therapy; Musculoskeletal pain

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