A 2012 study evaluated the oral cannabinoid nabilone (Cesamet) used as adjuvant to regular pain medications in 37 patients with diabetic neuropathy. 116 At 4 weeks, 70% of patients had at least a 30% reduction in pain. An open-label 5-week extension treatment period found a THC dose of 3 mg (range 1-4 mg) effective for continued pain reduction. 117 A small randomized cross-over trial in 16 patients with diabetic peripheral neuropathy compared the analgesic effects of three doses of inhaled cannabis (1% THC, 4% THC, or 7% THC) vs. placebo with pain sensitivity assessed after 4 hours. 117 Mean spontaneous pain scores (using 10-point scale) were modestly lower with all THC doses vs. placebo (-0.44 points with low dose, -0.42 points with medium dose, and -1.2 points with high dose, P<0.05 for all comparisons). Mean pain scores with evoked pain were only significant with high-dose THC (P<0.001). The percentage of patients with 30% or greater reductions in spontaneous pain were higher in the medium and high dose groups, but the differences with placebo did not reach statistical significance. Another trial randomized 30 patients with chronic painful diabetic neuropathy to a sublingual spray containing 27 mg/mL THC and 25 mg/mL CBD (Sativex) vs. placebo spray, both administered four times daily for 12 weeks. 118 No significant differences were reported for change in pain scores from baseline for superficial, deep, or muscular
pain, or in the percentages of patients reporting 30% or greater reductions in pain. An un-published clinical trial that randomized 297 patients with diabetic neuropathy to Sativex oromucosal spray (maximum daily dose of 65 mg THC and 60 mg CBD) vs. placebo for 14 weeks found no significant differences in pain intensity between groups. 119 None of the reviewed studies evaluated long- term efficacy and safety of cannabinoid exposure.
Fibromyalgia The European League Against Rheumatism (EULAR) guidelines for managing fibromyalgia- related pain recommend beginning with non-drug approaches (exercise, CBT, acupuncture, yoga, tai chi, and mindfulness) and then advancing to pharmacologic options (low dose amitriptyline, duloxetine or milnacipran, pregabalin). Most recommendations were considered weak, with the exception of exercise. 124 In the elderly, duloxetine or milnacipran and pregabalin or gabapentin may be the more favorable pharmacologic options. Non-drug options Movement-based options Exercise training is often recommended for patients with fibromyalgia, 125 not only for potential pain reductions, but for the other known physiologic benefits associated with exercise. The effects of exercise in fibromyalgia have been assessed in more than 30 trials, with the overall quality rated as moderate. 124 Some reviews have concluded that the strongest evidence was in support of aerobic exercise, 126 which is the current recommendation by the American College of Rheumatology. However, resistance training can be of benefit as well. 127 A 2017 Cochrane review of eight RCTs (n=456) comparing aerobic exercise training vs. no exercise or another type of intervention found small improvements (relative to comparators) in pain intensity (relative improvement 18%), stiffness (11.4%) and physical function (22%). 128
BEFORE MOVING ONTO THE NEXT SECTION, PLEASE COMPLETE CASE STUDY 3.
Other drug options Evidence for the SSRIs paroxetine and citalopram is inconsistent and insufficient to recommend their use in managing pain in diabetic neuropathy. However, these drugs may be effective if patients have coexisting pain and depression. 120 Earlier studies showed that treatment with topical capsaicin was beneficial for relieving pain in patients with diabetic neuropathy. 121,122 However, a 2017 meta-analysis of 5 randomized trials found that 0.075% capsaicin cream was no more effective than placebo (SMD -0.46; 95% CI: -0.95 to 0.03). 123
Case Study 3
Instructions: Spend 5 minutes reviewing the case below and considering the questions that follow.
Cassandra, 26, was diagnosed with type 1 diabetes at the age of 14. She presents with persistent burning pain in her lower extremities as well as numbness in her hands that make her work as a dental hygienist difficult. Recently, her family has noted that she seems to be stumbling at times. Cassandra has no history of diabetic retinopathy or nephropathy. She also denies resting tachycardia, orthostatic lightheadedness, early satiety, early morning nausea, changes in bowel habits, or postprandial sweating. She has a history of depression, which was treated with counseling and medication. She also notes menstrual irregularity, dysmenorrhea, and premenstrual emotional lability. She had been treated with oral contraceptives in the past, but had discontinued these 6–8 months ago. She had been prescribed a selective serotonin reuptake inhibitor (SSRI) for her pain symptoms as well as her depression, but she reports no relief of pain after 2 months. Her glycemic control has never been optimal despite a multiple-dose insulin program. Her hemoglobin A1C levels have typically been in the 8–9% range. Exam revealed a moderately overweight (BMI 27 kg/m 2 ) woman with a blood pressure of 138/85 mmHg with no orthostatic change and a resting pulse of 72. Laboratory testing revealed an A1C of 8.2%; an albumin-to-creatinine ratio of 25 μg/mg; and normal serum creatinine, complete blood count, total protein, sedimentation rate, and thyroid stimulating hormone.
1. What kinds of pharmacologic treatment options might you suggest for Cassandra?
2. Are there any non-pharmacologic approaches that might help relieve her symptoms?
3. What kinds of functional benchmarks might you set up to allow you and Cassandra to monitor progress, both in terms of pain and glycemic control?
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