Gabapentin improves cold-pressor pain responses in methadone-maintained patients

Abstract

Individuals on methadone maintenance for the treatment of addiction (MM) are demonstrated to be hyperalgesic to cold-pressor pain in comparison to matched controls and ex-opioid addicts, a finding described as clinical evidence of opioid-induced hyperalgesia (OIH). Interestingly, opioids induce hyperalgesia via many of the same neuro-inflammatory and central sensitization processes that occur with the development of neuropathic pain. Evaluated in this study was the efficacy of a key pharmacotherapy for neuropathic pain, gabapentin (GPN), to reverse OIH in MM patients. Utilizing a clinical trial design and double blind conditions, changes in cold-pressor pain threshold and tolerance following a five-week trial of GPN (titrated to 2400mg/day) were evaluated at peak and trough methadone plasma levels in a well-characterized MM sample. Drug abstinence was encouraged via an escalating payment schedule, and compliance monitored via pill counts and GPN plasma levels; entered into the analyses were only those subjects compliant and abstinent throughout the study (approx 45%). Utilizing change scores from baseline, significant improvements in coldpressor pain threshold and pain tolerance were observed at both peak and trough methadone levels (p < 0.05). Notably, drop-out rates due to medication side effects were low (2%) and the medication was well-tolerated. These results support that GPN, as prescribed for the treatment of neuropathic pain, is effective in decreasing OIH in patients who are abstinent and stable in methadone treatment.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

“…Thus far, a host of animal studies have found that OIH is reversible by the NMDA receptor antagonists MK-801 [31,42,[160][161][162][163][164][165], ketamine, or traxoprodil [93]. Human studies have found similar results by adding adjuvant ketamine [46,54,88,166], as well as gabapentinoids such as pregabalin [49,55] or gabapentin [23], or the cyclooxygenase-2 inhibitor parecoxib [48,167], as reviewed in the subsequent sections. However, more recent research has shown that manipulating these substrates does not unequivocally resolve OIH.…”

“…Several studies have demonstrated OIH in patients enrolled in methadone maintenance treatment [23,43,[57][58][59][60]. However, other studies have documented a reduction in OIH after patients were rotated onto methadone treatment.…”

“…While some studies suggest that OIH develops after chronic opioid use [41][42][43], both rodent [44,45] and human studies [46][47][48][49] have documented OIH within hours of acute opioid administration. Studies using shorter-acting opioids such as remifentanil, sufentanil, fentanyl, and morphine provide the most suspicion of OIH [49][50][51][52][53][54][55][56]; however, there is documentation of this phenomenon in patients receiving long-acting opioids (e.g., methadone or buprenorphine) as well [23,43,[57][58][59][60].…”

“…Secondly, the numerous populations under study likely influence the evaluation of OIH. Specifically, a majority of existing clinical studies of OIH focus on several cohorts: healthy volunteers receiving acute opioids while undergoing human experimental pain testing [62][63][64][65], those with acute pain following various surgical procedures [51-53, 66, 67], patients suffering from chronic pain [41,[68][69][70] or chronic illnesses such as cancer [50,[71][72][73][74], and populations of individuals with OUD [23,43,[57][58][59][60]. Third, OIH does not manifest in all patients receiving opioids; individual differences, including psychological factors, likely play a role in whether one develops OIH following opioid exposure, though research on this topic is needed.…”

“…Further, OIH may interfere with the patient's overall chronic pain treatment outcome and has the potential to propagate addiction. Thus, it has been suggested that OIH be considered a treatment target in addition to analgesia to ultimately improve management of patients treated with opioids [21][22][23].…”