_________________________________________________________________________ Neck Pain in Adults
at least 36 months [187]. Patient satisfaction with transdermal buprenorphine showed the same temporal pattern. Non- prescribed dose escalation (3%) was low, but patient motive (e.g., pain control, euphoria) was not analyzed. Dropout from ineffectiveness (4%) or adverse effects (12%, mostly skin irritation) exceeding similar trials [187]. Tramadol Tramadol is a weak opioid that also inhibits serotonin and noradrenaline reuptake, and it is an established option in chronic low back pain. Opioid and non-opioid mechanisms both act to produce analgesia, and account for its low “likeability” by drug misusers, with lower abuse potential than other opioids. It may also have anti-inflammatory activity. Tramadol use with other serotonergic medications (e.g., most antidepressants) may result in serotonin syndrome and should be avoided [71; 96; 157]. Tapentadol Tapentadol is a mu-opioid receptor agonist and norepinephrine reuptake inhibitor combined in a single molecule. Tapentadol extended-release was extensively investigated in Europe, with the finding that the formulation is effective in diverse chronic pain, with or without neuropathic pain component, in evaluations up to two years [192; 193]. Researchers found function, health status, and quality of life improved during long-term treatment. The drug has a good safety profile, with GI tolerability more favorable than other opioids and a low risk of withdrawal after cessation. To date, analgesic tolerance has not been found in long-term data. In studies, tapentadol was as effective as oxycodone in nociceptive and neuropathic chronic low back pain, with better GI tolerability and treatment adherence [71; 194; 195; 196]. Earlier gains in function, health status, and quality of life maintained over one year in 1,154 patients receiving open- label tapentadol extended-release after completing randomized controlled trials, including average pain scores (3.9 start, 3.7 end) [197]. As noted, few studies have evaluated opioid therapy, and pharmacotherapy in general, in chronic neck pain. However, an uncontrolled trial evaluated tapentadol extended-release in 54 patients with moderate-to-severe chronic neck pain over 12 weeks [4]. Participants’ reported pain-intensity scores (on 0–10 scale) were 1.7 resting (versus 6.8 at baseline) and 2.9 with movement (versus 8.8 at baseline). Approximately 89% of patients experienced ≥30% reduction in pain intensity on movement; 68% reported a ≥50% reduction. In addition, the average NDI score decreased from 55.6 at baseline to 19.7 after 12 weeks. Quality of sleep improved ≥30% in 79% of patients. Cervical range of motion was evaluated on flexion, extension, right and left lateral flexion, and rotation. Compared with baseline, patients with normal range of motion on flexion increased 13%; the other five measures increased 23% to 35% [4].
No patient dropped out from side effects, despite 90% being opioid-naïve on study entry. The average final dose was 204 mg/day, and tapentadol extended-release was well-tolerated in patients requiring 400 mg/day. Common side effects at 12 weeks were constipation and dizziness [4]. With further subject accrual, a second paper from this study compared tapentadol extended-release response in 94 patients with or without a neuropathic neck pain component. Both groups showed comparable reductions in neck pain intensity ≥30% (69% versus 70%) and in average pain scores from baseline (4.4 versus 4.8) at 4 weeks, and reduction in NDI scores from baseline to 12 weeks (46 to 13 versus 58 to 18) [198]. Results of one observational, retrospective study found that tapentadol extended-release resulted in improved sleep and quality of life in patients with moderate-to-severe chronic neck pain, with or without a neuropathic component [199]. Despite the limitations of uncontrolled trials, this data, together with studies in chronic low back pain, suggest tapentadol extended-release may be effective and tolerable for patients with chronic moderate-to-severe neck pain. The mu-opioid receptor binding affinity of tapentadol is 18-fold lower than morphine, suggesting lower abuse potential than standard opioids (confirmed by several studies) [96; 200]. In 113,914 individuals assessed for substance abuse treatment, tapentadol abuse was lowest overall and significantly lower than other prescribed oral opioids. Adjusted for nationwide prescription volume, tapentadol abuse liability was the second lowest, after only tramadol [201]. Among 1.9 million messages posted by recreational drug users on online forums, the proportion of discussions and endorsements for abuse were substantially lower for tapentadol than comparator drugs [202]. Data from drug diversion databases and investigators and anonymous street drug pricing websites indicate illicit sales and use of tapentadol extended-release was rare. In the few cases of illicit sales, tapentadol extended-release was 10% the
price of standard opioids [203]. Cebranopadol and NKTR-181
Two novel opioid analgesics designed to improve safety over standard opioids are in pre-approval evaluation. Cebranopadol is a mu-opioid receptor agonist and nociceptin/orphanin FQ peptide receptor agonist that may improve respiratory depression safety. A 14-week study in chronic low back pain found cebranopadol comparable to tapentadol in analgesic efficacy and sleep and functional improvements [204]. Oxycodegol (NKTR-181) is a long-acting mu-opioid receptor agonist with structural properties that alter its brain-entry kinetics and may limit abuse potential [175]. Initial studies involving patients with chronic low back pain have found improvements in pain score and sleep compared with placebo [205]. In January 2020, the FDA rejected approval for the new drug application for oxycodegol, raising concerns about the drug’s potential for misuse or abuse [206; 207].
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