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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
1. Andersson HI, Ejlertsson G, Leden I, et al. Musculoskeletal chronic pain in general practice. Studies of health care utilisation in comparison with pain prevalence. Scand J Prim Health Care
2. Badley EM, Rasooly I, Webster GK. Relative importance of musculoskeletal disorders as a cause of chronic health problems, disability, and health care utilization: findings from the 1990 Ontario Health Survey. J Rheumatol
3. Crombie IK, Croft PR, Linton SJ, et al. Epidemiology of pain. Seattle: IASP Press, 1999.
4. De Winter AF, Jans MP, Scholten RJ, et al. Diagnostic classification of shoulder disorders: interobserver agreement and determinants of disagreement. Ann Rheum Dis
5. Bamji AN, Erhardt CC, Price TR, et al. The painful shoulder: can consultants agree? Br J Rheumatol
6. Calis M, Akgün K, Birtane M, et al. Diagnostic values of clinical diagnostic tests in subacromial impingement syndrome. Ann Rheum Dis
7. Croft P. Diagnosing regional pain: the view from primary care. Baillieres Clin Rheumatol
8. Lane NE, Thompson JM. Management of osteoarthritis in the primary-care setting: an evidence-based approach to treatment. Am J Med
9. Koes BW, Scholten RJPM, Mens JMA, et al. Efficacy of epidural steroid injections for low-back pain and sciatica: a systematic review of randomized clinical trials. Pain
10. Watts RW, Silagy CA. A meta-analysis on the efficacy of epidural corticosteroids in the treatment of sciatica. Anaesth Intensive Care
11. McQuay HJ, Moore A. Epidural steroids for sciatica. Anaesth Intensive Care
12. Carette S, Leclaire R, Marcoux S, et al. Epidural corticosteroid injections for sciatica due to herniated nucleus pulposus. N Eng J Med
13. Yates DW. A comparison of the types of epidural injection commonly used in the treatment of low back pain and sciatica. Rheumatol Rehabil
14. Mathews JA, Mills SB, Jenkins VM, et al. Back pain and sciatica: controlled trials of manipulation, traction, sclerosant and epidural injections. Br J Rheumatol
15. Czarski Z. Treatment of sciatica with hydrocortisone and novocaine injections into the sacral hiatus. Przegl Lek
16. Beliveau P. A comparison between epidural anaesthesia with and without corticosteroid in the treatment of sciatica. Rheumatol Phys Med
17. Bush K, Hillier S. A controlled study of caudal epidural injections of triamcinolone plus procaine for the management of intractable sciatica. Spine
18. Breivik H, Hesla PE, Molnar I, et al. Treatment of chronic low back pain and sciatica. Comparison of caudal epidural injections of bupivacaine and methylprednisolone with bupivacaine followed by saline. In: Bonica JJ, Albe-Fessard D, eds. Advances in pain research and therapy.
New York: Raven Press; 1976:927-32.
19. White AH, Derby R, Wynne G. Epidural injections for the diagnosis and treatment of low-back pain. Spine
20. Chandani A, Waldron D, Teng SS, et al. A systematic review of treatments for "tennis elbow." Aust Musculoskeletal Med
21. Labelle H, Guibert R, Joncas J, et al. Lack of scientific evidence for the treatment of lateral epicondylitis of the elbow. An attempted meta-analysis. J Bone Joint Surg Br
22. Assendelft WJ, Hay EM, Adshead R, et al. Corticosteroid injections for lateral epicondylitis: a systematic overview. Br J Gen Pract
23. Verhaar JA, Walenkamp GH, van Mameren H, et al. Local corticosteroid injection versus Cyriax-type physiotherapy for tennis elbow. J Bone Joint Surg Br
24. Van der Heijden GJ, Van der Windt DA, Kleijnen J, et al. Steroid injections for shoulder disorders: a systematic review of randomized clinical trials. Br J Gen Pract
25. Green S, Buchbinder R, Glazier R, Forbes A. Systematic review of randomised controlled trials of interventions for painful shoulder: selection criteria, outcome assessment, and efficacy. BMJ
26. Vecchio PC, Hazleman BL, Kong RH. A double-blind trial comparing subacromial methylprednisolone and lignicaine in acute rotator cuff tendinitis. Br J Rheumatol
27. Withrington RH, Girgis FL, Seifert MH. A placebo-controlled trial of steroid injections in the treatment of supraspinatus tendonitis. Scand J Rheumatol
28. Rizk TE, Pinals RS, Talaiver AS. Corticosteroid injections in adhesive capsulitis: investigation of their value and site. Arch Phys Med Rehabil
29. Van der Windt DA, Koes BW, Devillé W, et al. Effectiveness of corticosteroid injections versus physiotherapy for treatment of painful stiff shoulder in primary care: randomised trial. BMJ
30. Dieppe PA, Sathapatayavongs B, Jones HE, et al. Intra-articular steroids in osteoarthritis. Rheumatol Rehabil
31. Barnsley L, Lord SM, Wallis BJ, et al. Lack of effect of intraarticular corticosteroids for chronic pain in the cervical zygapophyseal joints. N Eng J Med
32. Carette S, Marcoux S, Truchon R, et al. A controlled trial of corticosteroid injections into facet joints for chronic low back pain. N Eng J Med
33. Labelle H, Guibert R. Efficacy of diclofenac in lateral epicondylitis of the elbow also treated with immobilization. The University of Montreal Orthopaedic Research Group. Arch Fam Med
34. Burton AK. A comparative trial of forearm strap and topical anti-inflammatory as adjuncts to manipulative therapy in tennis elbow. Man Med
35. Van der Windt DA, Van der Heijden GJ, Scholten RJ, et al. The efficacy of non-steroidal anti-inflammatory drugs (NSAIDS) for shoulder complaints. A systematic review. J Clin Epidemiol
36. Petri M, Dobrow R, Neiman R, et al. Randomized, double-blind, placebo-controlled study of the treatment of the painful shoulder. Arthritis Rheum
37. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetominophen in a two-year study of treatment of osteoarthritis of the knee. Ann Rheum Dis
38. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Eng J Med
39. Bentley G, Leslie IJ, Fischer D. Effect of aspirin treatment on chondromalacia patellae. Ann Rheum Dis
40. Moore RA, Tramer MR, Carroll D, et al. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ
41. Spitzer WO, Skovron ML, Salmi LR. Scientific monograph of the Quebec Task Force on whiplash-associated disorders: Redefining 'whiplash' and its management. Spine
42. Aker PD, Gross AR, Goldsmith CH, et al. Conservative management of mechanical neck pain: systematic overview and metaanalysis. BMJ
43. Coletta R, Maggiolo F, Di Tizio S. Etofenamate and transcutaneous electrical nerve stimulation treatment of painful spinal syndromes. Int J Clin Pharmacol Res
44. Koes BW, Scholten RJ, Mens JM, et al. Efficacy of non-steroidal anti-inflammatory drugs for low back pain: a systematic review of randomised clinical trials. Ann Rheum Dis
45. Van Tulder MW, Koes BW, Bouter LM. Conservative treatment of acute and chronic nonspecific low back pain. A systematic review of randomized controlled trials of the most common interventions. Spine
46. Emery P, Zeidler H, Kvien TK, et al. Celecobix versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet
47. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc
48. Kaplan-Machlis B, Klostermeyer BS. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann Pharmacother
49. Savage SR. Opioid therapy for chronic pain: assessment of consequences. Acta Anaesthesiol Scand
50. Moulin DE, Iezzi A, Amireh R, et al. Randomised trial of oral morphine for chronic non-cancer pain. Lancet
51. Jamison RN, Raymond SA, Slawsby EA, et al. Opioid therapy for chronic noncancer back pain. A randomized prospective study. Spine
52. Turner JA, Denny MC. Do antidepressant medications relieve chronic low back pain? J Fam Pract
53. Alcoff J, Jones E, Rust P, et al. Controlled trial of imipramine for chronic low back pain. J Fam Pract
54. Pheasant H, Bursk A, Goldfarb J, et al. Amitriptyline and chronic low-back pain. A randomized double-blind crossover study. Spine
55. Goodkin K, Gullion CM, Agras WS. A randomized, double-blind, placebo-controlled trial of trazodone hydrochloride in chronic low back pain syndrome. J Clin Psychopharmacol
56. Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low back pain. J Int Med Res
57. Atkinson JH, Slater MA, Williams RA, et al. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back pain. Pain
58. Atkinson JH, Slater MA, Wahlgren DR, et al. Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity. Pain
59. Bercel NA. Cyclobenzaprine in the treatment of skeletal muscle spasm in osteoarthritis of the cervical and lumbar spine. Curr Ther Res Clin Exp
60. Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies. Arch Phys Med Rehabil
61. George E. Intra-articular hyaluronan treatment for osteoarthritis. Ann Rheum Dis
62. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis. The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheum Dis Clin North Am
63. Maheu E, Mazieres B, Valat JP, et al. Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum
64. Parnham MJ. Antirheumatic agents and leukocyte recruitment. New light on the mechanism of action of oxaceprol. Biochem Pharmacol
65. Bauer HW, Klasser M, von Hanstein KL, et al. Oxaceprol is as effective as diclofenac in the therapy of osteoarthritis of the knee and hip. Clin Rheumatol
66. Nicolas P, Tod M, Padoin C, et al. Clinical pharmacokinetics of diacerein. Clin Pharmacokinet
67. Spencer CM, Wilde MI. Diacerein. Drugs
68. Weiner BK, Fraser RD. Foraminal injection for lateral lumbar disc herniation. J Bone Joint Surg Br
69. Lutz GE, Vad VB, Wisneski RJ. Fluoroscopic transforaminal lumbar epidural steroids: an outcome study. Arch Phys Med Rehabil
70. Riew KD, Yin Y, Gigula L, et al. Can nerve root injections obviate the need for operative treatment of lumbar radicural pain? A prospective, randomized, controlled, double-blinded study. North American Spine Society, October 20-23, 1999;14th Meeting: 94-5.
71. Langerman L, Golomb E, Benita S. Spinal anesthesia: significant prolongation of the pharmacologic effect of tetracaine with lipid solution of the agent. Anesthesiology
72. Masters DB, Berde CB, Dutta S, et al. Sustained local anesthetic release from bioerodible polymer matrices: a potential method for prolonged regional anesthesia. Pharm Res
73. Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature
74. Koelbaek Johansen M, Graven-Nielsen T, et al. Generalised muscular hyperalgesia in chronic whiplash syndrome. Pain
75. Sheather Reid RB, Cohen ML. Psychophysical evidence for a neuropathic component of chronic neck pain. Pain
76. Sörensen J, Graven Nielsen T, Henriksson KG, et al. Hyperexcitability in fibromyalgia. J Rheumatol
77. Woolf CJ. Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain
78. Dahl JB, Brennum J, Arendt-Nielsen L, et al. The effect of preversus postinjury infiltration with lidocaine on thermal and mechanical hyperalgesia after heat injury to the skin. Pain
79. Dubner R, Ren K. Endogenous mechanisms of sensory modulation. Pain
80. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology
81. Martin WJ, Loo CM, Basbaum AI. Spinal cannabinoids are antiallodynic in rats with persistent inflammation. Pain
82. Li J, Daughters RS, Bullis C, et al. The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats. Pain
83. Smith FL, Cichewicz D, Martin ZL, et al. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacol Biochem Behav
84. Berenbaum MC. What is synergy? Pharm Rev
85. Curatolo M, Schnider TW, Petersen-Felix S, et al. A direct search procedure to optimize combinations of epidural bupivacaine, fentanyl, and clonidine for postoperative analgesia. Anesthesiology
86. Fisher DM. The direct search procedure: a new approach to evaluating clinical regimens. Anesthesiology