Angela Mailis-Gagnon

Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects

Background: Chronic noncancer pain (CNCP) is a major health problem, for which opioids provide one treatment option. However, evidence is needed about side effects, efficacy, and risk of misuse or addiction. Methods: This meta-analysis was carried out with these objectives: to compare the efficacy of opioids for CNCP with other drugs and placebo; to identify types of CNCP that respond better to opioids; and to determine the most common side effects of opioids. We searched MEDLINE, EMBASE, CENTRAL (up to May 2005) and reference lists for randomized controlled trials of any opioid administered by oral or transdermal routes or rectal suppositories for CNCP (defined as pain for longer than 6 mo). Extracted outcomes included pain, function or side effects. Methodological quality was assessed with the Jadad instrument; analyses were conducted with Revman 4.2.7. Results: Included were 41 randomized trials involving 6019 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. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1–16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant. Interpretation: Weak and strong opioids outperformed placebo for pain and function in all types of CNCP. Other drugs produced better functional outcomes than opioids, whereas for pain relief they were outperformed only by strong opioids. Despite the relative shortness of the trials, more than one-third of the participants abandoned treatment.

Opioids Compared With Placebo or Other Treatments for Chronic Low Back Pain An Update of the Cochrane Review

Study Design. Systematic review and meta-analysis. Objective. To assess the efficacy of opioids in adults with chronic low back pain (CLBP). Summary of Background Data. Opioids for CLBP has increased dramatically. However, the benefits and risks remain unclear. Methods. We updated a 2007 Cochrane Review through October 2012 of randomized controlled trials from multiple databases. Use of noninjectable opioids in CLBP for at least 4 weeks was compared with placebo or other treatments; comparisons with different opioids were excluded. Outcomes included pain and function using standardized mean difference (SMD) or risk ratios with 95% confidence intervals (CIs), and absolute risk difference with 95% CI for adverse effects. Study quality was evaluated using Grading of Recommendations Assessment, Development, and Evaluation criteria. Results. Fifteen trials (5540 participants), including twelve new, met the criteria. Tramadol was better than placebo for pain (SMD, −0.55; 95% CI, −0.66 to −0.44) and function (SMD, −0.18; 95% CI, −0.29 to −0.07). Compared with placebo, transdermal buprenorphine decreased pain (SMD, −2.47; 95% CI, −2.69 to −2.25), but not function (SMD, −0.14; 95% CI, −0.53 to 0.25). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol), were better than placebo for pain (SMD, −0.43; 95% CI, −0.52 to −0.33) and function (SMD, −0.26; 95% CI, −0.37 to −0.15). One trial demonstrated little difference with tramadol compared with celecoxib for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for pain or function. Reviewed trials had low to moderate quality, high drop-out rates, short duration, and limited interpretability of functional improvement. No serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism) were reported. Conclusion. There is evidence of short-term efficacy (moderate for pain and small for function) of opioids to treat CLBP compared with placebo. The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven. Level of Evidence: 1

A Comparison between Enriched and Nonenriched Enrollment Randomized Withdrawal Trials of Opioids for Chronic Noncancer Pain

BACKGROUND An enriched enrollment randomized withdrawal (EERW) design excludes potential participants who are nonresponders or who cannot tolerate the experimental drug before random assignment. It is unclear whether EERW design has an influence on the efficacy and safety of opioids for chronic noncancer pain (CNCP). OBJECTIVES The primary objective was to compare the results from EERW and non-EERW trials of opioids for CNCP. Secondary objectives were to compare weak versus strong opioids, subgroups of patients with different types of pain, and the efficacy of opiods compared with placebo versus other drugs. METHODS MEDLINE, EMBASE and CENTRAL were searched up to July 2009, for randomized controlled trials of any opioid for CNCP. Metaanalyses and meta-regressions were conducted to compare the results. Treatment efficacy was assessed by effect sizes (small, medium and large) and the incidence of adverse effects was assessed by a clinically relevant mean difference of 10% or greater. RESULTS Sixty-two randomized trials were included. In 61 trials, the duration was less than 16 weeks. There was no difference in efficacy between EERW and non-EERW trials for both pain (P=0.6) and function (P=0.3). However, EERW trials failed to detect a clinically relevant difference for nausea, vomiting, somnolence, dizziness and dry skin⁄itching compared with non-EERW. Opioids were more effective than placebo in patients with nociceptive pain (effect size=0.60, 95% CI 0.49 to 0.72) and neuropathic pain (effect size=0.56, 95% CI 0.38 to 0.73). CONCLUSION EERW trial designs appear not to bias the results of efficacy, but they underestimate the adverse effects. The present updated meta- analysis shows that weak and strong opioids are effective for CNCP of both nociceptive and neuropathic origin.

Systematic Review of the Quality and Generalizability of Studies on the Effects of Opioids on Driving and Cognitive/Psychomotor Performance

Introduction:The effect of opioids on driving performance has been much debated. Driving is a complex task requiring integration of psychomotor, cognitive, motor and decision-making skills, visual-spatial abilities, divided attention, and behavioral and emotional control. The objective of this systematic review was to assess the quality of studies and to revisit the concept that patients on stable opioids are safe to drive as it applies to everyday practice. Methods:We searched MEDLINE, EMBASE, PSYCinfo, CENTRAL, TRANSPORT, CINAHL, reference lists of retrieved articles and narrative reviews, for studies on chronic cancer and noncancer pain patients on opioids, tested by driving, driving simulator, or cognitive/psychomotor tests. Methodological quality was assessed with Methodological Index for Nonrandomized Studies, cognitive/psychomotor tests were appraised regarding their sensitivity and validation, and whether confounding variables potentially affecting the study conclusions were recorded. The results were analyzed both quantitatively and qualitatively. Results:We included 35 studies (2044 patients, 1994 controls), 9% of the studies were of poor, 54% of fair, and 37% of high quality; 3 quarters of the studies used high sensitivity cognitive tests. Amount and dose of opioids varied largely in many studies. Mean number of possible but unreported confounders was 2.2 (range, 0 to 4), relating to failure of the studies to mention coprescriptions with psychotropic effects, pain severity, sleep disorder or daytime somnolence, and/or significant depressive or anxiety-related problems. Interpretation:The commonly held concept that “chronic pain patients on stable opioids are safe to drive” cannot be generalized to all such patients in everyday practice, but may be applicable only to a subset who meet certain criteria.

Oral methadone for chronic noncancer pain: a systematic literature review of reasons for administration, prescription patterns, effectiveness, and side effects

Objective:To assess the indications, prescription patterns, effectiveness, and side effects of oral methadone for the treatment of chronic noncancer pain. Methods:We conducted searches of several electronic databases, textbooks and reference lists for controlled or uncontrolled studies in humans. Effectiveness was assessed using a dichotomous classification of “meaningful” versus “nonmeaningful” outcomes. Results:Twenty-one papers (1 small randomized trial, 13 case reports, and 7 case series) involving 545 patients with multiple noncancer pain conditions were included. In half of the patients, no specific diagnosis was reported. Methadone was administered primarily when previous opioid treatment was ineffective or produced intolerable side effects. Starting dose ranged from 0.2 to 80 mg/day and maximum dose ranged from 20 to 930 mg/day. Pain outcomes were meaningful in 59% of the patients in the uncontrolled studies. The randomized trial demonstrated a statistically significant improvement in pain for methadone (20 mg/day) compared to placebo. Side effects were considered minor. Discussion:Oral methadone is used for various noncancer pain syndromes, at different settings and with no prescription pattern that could be identifiable. Starting, maintenance, and maximum doses showed great variability. The figure of 59% effectiveness of methadone should be interpreted very cautiously, as it seems overrated due to the poor quality of the uncontrolled studies and their tendency to report positive results. The utilization of oral methadone for noncancer pain is based on primarily uncontrolled literature. Well-designed controlled trials may provide more accurate information on the drugs efficiency in pain syndromes and in particular neuropathic pain.

Posttraumatic painful torticollis.

The development of abnormal posturing of the neck or shoulder after local injury has been termed posttraumatic cervical dystonia (PTCD). Certain features seem to distinguish a unique subgroup of patients with this disorder from those with features more akin to typical idiopathic cervical dystonia, such as onset and maximum disability that occurs very quickly after injury, severe pain and a fixed abnormal posture. In an attempt to clarify the nature of this syndrome further, we evaluated 16 such patients (8 men, 8 women). Motor vehicle accident and work‐related injuries were common precipitants, with posturing usually developing shortly after trauma, and little progression occurring after the first week. A characteristic, painful, fixed head tilt and shoulder elevation were present in all but one patient, who had a painless elevated shoulder and painful contralateral shoulder depression, as well as nondermatomal sensory loss in 14 patients. Additional abnormalities included dystonic posturing in a limb (2 patients) or jaw (1 patient), limb tremor (3 patients) and “give‐way” limb weakness (8 patients). The tremor and the jaw dystonia demonstrated features suggestive of a psychogenic movement disorder, most commonly distractibility. Litigation or compensation was present in all 16 patients. Intravenous sodium amytal improved the posture, pain or both in 13 of 13 patients; in 7 of 13 the sensory deficit either markedly improved or normalized. General anesthesia demonstrated full range of motion in all 5 patients assessed. Psychological evaluations suggested that psychological conflict, stress, or both were being expressed via somatic channels in 11 of 12 tested patients. Our results suggest an important role of psychological factors in the etiology or maintenance of abnormal posture, pain and associated disability of these patients. The role of central factors triggered in psychologically vulnerable individuals after physical trauma is discussed. We propose that the disorder be referred to as “posttraumatic painful torticollis” rather than characterize it as a form of dystonia until further information on its pathogenesis is forthcoming.

Pain characteristics and demographics of patients attending a university-affiliated pain clinic in Toronto, Ontario

BACKGROUND Pain clinics tend to see more complex chronic pain patients than primary care settings, but the types of patients seen may differ among practices. OBJECTIVE The aim of the present observational study was to describe the pain and demographic characteristics of patients attending a university-affiliated tertiary care pain clinic in Toronto, Ontario. METHODS Data were collected on 1242 consecutive new patients seen over a three-year period at the Comprehensive Pain Program in central Toronto. RESULTS Musculoskeletal problems affecting large joints and the spine were the predominant cause of pain (more prevalent in women), followed by neuropathic disorders (more prevalent in men) in patients with recognizable physical pathology. The most affected age group was in the 35- to 49-year age range, with a mean pain duration of 7.8 years before the consultation. While 77% of the Comprehensive Pain Program patients had relevant and detectable physical pathology for pain complaints, three-quarters of the overall study population also had significant associated psychological or psychiatric comorbidity. Women, in general, attended the pain clinic in greater numbers and had less apparent physical pathology than men. Finally, less than one in five patients was employed at the time of referral. CONCLUSIONS The relevance of the data in relation to other pain clinics is discussed, as well as waiting lists and other barriers faced by chronic pain patients, pain practitioners and pain facilities in Ontario and Canada.

Abnormal contralateral pain responses from an intradermal injection of phenylephrine in a subset of patients with complex regional pain syndrome (CRPS)

Abstract We have examined the effect of an intradermal injection of phenylephrine (1 mg/0.1 ml), an alpha‐1‐adrenoceptor agonist in normal subjects, and patients with sympathetically‐independent (SIP) and sympathetically‐maintained pain (SMP). Normal subjects and SIP patients experienced only brief stinging pain, while subsets of both sympathectomized and non‐sympathectomized SMP patients (6/9 and 4/8, respectively) experienced an additional abnormal pain response accompanied by mechano‐allodynia around the injection site. Both the normal and abnormal pain response after intradermal phenylephrine are similar to those observed with intradermal norepinephrine. In contrast to previous reports in the literature, we found that three sympathectomized SMP patients (who, however, had failed to experience pain relief after surgical sympathectomy despite very good relief after sympathetic blocks) also experienced abnormal pain and mechano‐allodynia when phenylephrine was injected to a limb contralateral to the symptomatic sympathectomized extremity. Abnormal pain response evoked by norepinephrine or phenylephrine injection in the ipsilateral symptomatic limb of SMP patients may be due to injury‐evoked nociceptor responsiveness to catecholamines. However, such a response in contralateral asymptomatic limbs suggests an additional factor that more likely than not is of central origin and may or may not be related to sympathectomy and its success or failure to treat pain.

Characteristics and Period Prevalence of Self-induced Disorder in Patients Referred to a Pain Clinic With the Diagnosis of Complex Regional Pain Syndrome

IntroductionAlthough there have been a few case reports in the literature of self-inflicted symptoms presenting as complex regional pain syndrome (CRPS), there has been no systematic study. This report investigates the period prevalence and characteristics of self-induced disorders in patients referred to a comprehensive pain clinic with a diagnosis of CRPS. MethodsRetrospective chart review was conducted for all cases referred as “neuropathic pain” to a comprehensive pain clinic over a period of 2 years. ResultsOut of 175 consecutive neuropathic pain referrals over a 2-year period, 41 were specifically referred as CRPS. Application of (modified) 1994 IASP CRPS criteria confirmed the diagnosis of CRPS in 11/15 men and in 15/26 women. Four of the 15 women had evidence of active self-induced signs and symptoms (eg, ligation of the limb, ulcerations, bizarre migrating wounds), which abated with casting, strict observation, discussion with the patient, or other intervention. The characteristics of these cases are presented and compared with other similar cases seen in previous years. ConclusionsThis is the first report of a case series of patients diagnosed as CRPS with self-induced symptoms. We discuss in detail limitations of the study, factors that contribute to the index of suspicion, and the complex nature of the behavior including the overlap between factitious disorder, somatoform disorders, and malingering, whereas we stress the legitimacy of CRPS as a diagnosis.

Pain characteristics of adults 65 years of age and older referred to a tertiary care pain clinic

BACKGROUND Reports indicate that characteristics of older adults with chronic pain may be different than those of younger persons. OBJECTIVE To study the pain characteristics of older patients presenting to a tertiary pain clinic for the first time. METHODS Age, sex and relative contributions of biomedical versus psychosocial variables contributing to chronic pain were investigated in patients 65 years of age and older, in comparison with younger patients, from a sample of 1242 consecutive new patients attending a tertiary care pain clinic. The presence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision somatoform pain disorders were defined, using an explicated method of ascertaining the biomedical and psychological variables underlying the pain complaints. RESULTS The older patients (14.7% of the total sample) had relatively more physical problems (concordant with their complaints) but fewer psychological factors contributing to disability than the younger pain patients. Musculoskeletal and neuropathic disorders affected 40.7% and 35.2% of the older patients, respectively, while several patients had more than one painful disorder. Musculoskeletal problems were more prevalent in the women, and neuropathic problems were more prevalent in the men. CONCLUSIONS The older pain patients are a distinct group. Factors affecting the delayed presentation of older pain patients to the pain clinic and limitations of the present study are discussed.