Morphine, nortriptyline and their combination vs. placebo in patients with chronic lumbar root pain

Abstract

Although lumbar radicular pain is the most common chronic neuropathic pain syndrome, there have been few randomized studies of drug treatments. We compared the efficacy of morphine (15-90 mg), nortriptyline (25 -100 mg), their combination, and a benztropine "active placebo" (0.25-1 mg) in patients with chronic sciatica. Each period consisted of 5 weeks of dose escalation, 2 weeks of maintenance at the highest tolerated doses, and 2 weeks of dose tapering. The primary outcome was the mean daily leg pain score on a 0-10 scale during the maintenance period. Secondary outcomes included a 6-point ordinal global pain relief scale, the Beck Depression Inventory (BDI), the Oswestry Back Pain Disability Index (ODI) and the SF-36. In the 28 out of 61 patients who completed the study, none of the treatments produced significant reductions in average leg pain or other leg or back pain scores. Pain reduction, relative to placebo treatment was 14% for nortriptyline (95% CI= [−2%, 30%]), 7% for morphine (95% CI= [−8%, 22%]), and 7% for the combination treatment (95% CI= [−4%, 18%]). Mean doses were: nortriptyline alone, 84 +/− 24.44 (SD)mg/day; morphine alone, 62 +/−29mg/day; and combination, morphine, 49 +/−27 mg/day plus nortriptyline, 55 mg+/− 33.18 mg/ day. Over half of the study completers reported some adverse effect with morphine, nortriptyline or their combination. Within the limitations of the modest sample size and high dropout rate, these results suggest that nortriptyline, morphine and their combination may have limited effectiveness in the treatment of chronic sciatica.

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

“…In 3 RCTs, there was no evidence of efficacy of nortriptyline, 84 amitriptyline, 85 or gabapentin. 86 Finally, recent trials of nortriptyline and morphine and their combination 70 and pregabalin 87 and an equivocal trial of topiramate 88 suggest that lumbosacral radiculopathy might be a third peripheral NP condition that is relatively refractory to existing first-and second-line medications. Interestingly, patients with failed back surgery syndrome, many of whom have lumbosacral radiculopathy, appear to respond to spinal cord stimulation, 89 which suggests that this NP condition is not generally refractory to all treatment modalities.…”

Treatment Considerations for Patients With Neuropathic Pain and Other Medical Comorbidities

“…20 In patients with lumbar root pain, morphine, nortriptyline, and their combination failed to provide significant reduction in average leg pain. 21 Mechanisms of action and dosing of the first-line NP drugs and opioids are presented in Table 1. The TCAs, duloxetine, and venlafaxine are not recommended in patients with prostatic hypertrophy and/or urinary retention, whereas they are reasonable for patients with overactive bladder.…”

Pharmacotherapy of low back pain: targeting nociceptive and neuropathic pain components

“…However, it may not be valid to extrapolate opioid effectiveness in neuropathic pain from other causes to effectiveness in radiculopathy. The only study specifically examining opioid effectiveness (oral morphine) in patients with radicular pain was small (n ¼ 55), experienced a very high dropout rate (number completing ¼ 28) and failed to demonstrate any significant difference compared with placebo on ratings of leg pain 80 . Further large-scale randomized controlled trials will be required to resolve this issue.…”

“…The majority of original research papers published in the last 10 years have failed to show a benefit for antidepressants in chronic LBP. In a comparison of morphine, nortriptyline and their combination, nortriptyline was shown to be ineffective for reduction of leg pain scores in patients with sciatica (n ¼ 55), a surprising finding given the efficacy of TCAs in other neuropathic syndromes, including painful diabetic neuropathy and postherpetic neuralgia 80 . Overall, 68% of nortriptyline patients reported an AE, most commonly dry mouth or constipation 80 .…”

“…In a comparison of morphine, nortriptyline and their combination, nortriptyline was shown to be ineffective for reduction of leg pain scores in patients with sciatica (n ¼ 55), a surprising finding given the efficacy of TCAs in other neuropathic syndromes, including painful diabetic neuropathy and postherpetic neuralgia 80 . Overall, 68% of nortriptyline patients reported an AE, most commonly dry mouth or constipation 80 . A sustained-release formulation of the noradrenaline and dopamine reuptake inhibitor bupropion failed to show any benefit over placebo in patients with chronic LBP, although the majority of patients (41/44) had pain of a non-neuropathic origin in this study 92 .…”