Preliminary results from a randomized, controlled, cross-over trial of intrathecal oxytocin for neuropathic pain.

OBJECTIVE: Compare intrathecal oxytocin, 100 µg to placebo on ongoing neuropathic pain and mechanical hyperalgesia and allodynia. STUDY DESIGN: Randomized, controlled, double-blind cross-over. SETTING: Clinical research unit. SUBJECTS: Individuals aged 18 to 70 years with neuropathic pain for at least 6 months. METHODS: Individuals received intrathecal injections of oxytocin and saline, separated by at least 7 days, and ongoing pain in neuropathic area (VAS [visual analog scale]) and areas of hypersensitivity to von Frey filament and cotton wisp brushing were measured for 4 hours. Primary outcome was VAS pain in the first 4 hours after injection, analyzed by linear mixed effects model. Secondary outcomes were verbal pain intensity scores at daily intervals for 7 days and areas of hypersensitivity and elicited pain for 4 hours after injections. RESULTS: The study was stopped early after completion of 5 of 40 subjects planned due to slow recruitment and funding limitations. Pain intensity prior to injection was 4.75 ± 0.99 and modeled pain intensity decreased more after oxytocin than placebo to 1.61 ± 0.87 and 2.49 ± 0.87, respectively (P = .003). Daily pain scores were lower in the week following injection of oxytocin than saline (2.53 ± 0.89 vs 3.66 ± 0.89; P = .001). Allodynic area decreased by 11%, but hyperalgesic area increased by 18% after oxytocin compared to placebo. There were no study drug related adverse effects. CONCLUSION: Although limited by the small number of subjects studied, oxytocin reduced pain more than placebo in all subjects. Further study of spinal oxytocin in this population is warranted. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on 03/27/2014 (NCT02100956). The first subject was studied on 06/25/2014.

Randomized controlled trial of intrathecal oxytocin on speed of recovery after hip arthroplasty.

ABSTRACT: Recovery from surgery is quicker in the postpartum period, and this may reflect oxytocin action in the spinal cord. We hypothesized that intrathecal injection of oxytocin would speed recovery from pain and disability after major surgery. Ninety-eight individuals undergoing elective total hip arthroplasty were randomized to receive either intrathecal oxytocin (100 µg) or saline. Participants completed diaries assessing pain and opioid use daily and disability weekly, and they wore an accelerometer beginning 2 weeks before surgery until 8 weeks after. Groups were compared using modelled, adjusted trajectories of these measures. The study was stopped early due to the lack of funding. Ninety patients received intrathecal oxytocin (n = 44) or saline (n = 46) and were included in the analysis. There were no study drug-related adverse effects. Modelled pain trajectory, the primary analysis, did not differ between the groups, either in pain on day of hospital discharge (intercept: -0.1 [95% CI: -0.8 to 0.6], P = 0.746) or in reductions over time (slope: 0.1 pain units per log of time [95% CI: 0-0.2], P = 0.057). In planned secondary analyses, postoperative opioid use ended earlier in the oxytocin group and oxytocin-treated patients walked nearly 1000 more steps daily at 8 weeks ( P < 0.001) and exhibited a clinically meaningful reduction in disability for the first 21 postoperative days ( P = 0.007) compared with saline placebo. Intrathecal oxytocin before hip replacement surgery does not speed recovery from worst daily pain. Secondary analyses suggest that further study of intrathecal oxytocin to speed functional recovery without worsening pain after surgery is warranted.

Patterns of recovery from pain after cesarean delivery.

We know very little about the change in pain in the first 2 months after surgery. To address this gap, we studied 530 women scheduled for elective cesarean delivery who completed daily pain diaries for 2 months after surgery through text messaging. Over 82% of subjects missed fewer than 10 diary entries and were included in the analysis. Completers were more likely to be Caucasian, nonsmokers, and with fewer previous pregnancies than noncompleters. Daily worst pain intensity ratings for the previous 24 hours were fit to a log(time) function and allowed to change to a different function up to 3 times according to a Bayesian criterion. All women had at least one change point, occurring 22 ± 9 days postoperatively, and 81% of women had only one change, most commonly to a linear function at 0 pain. Approximately 9% of women were predicted to have pain 2 months after surgery, similar to previous observations. Cluster analysis revealed 6 trajectories of recovery from pain. Predictors of cluster membership included severity of acute pain, perceived stress, surgical factors, and smoking status. These data demonstrate feasibility but considerable challenges to this approach to data acquisition. The form of the initial process of recovery from pain is common to all women, with divergence of patterns at 2 to 4 weeks after cesarean delivery. The change-point model accurately predicts recovery from pain; its parameters can be used to assess predictors of speed of recovery; and it may be useful for future observational, forecasting, and interventional trials.

Day-to-day experience in resolution of pain after surgery.

We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another.

Failure of intrathecal ketorolac to reduce remifentanil-induced postinfusion hyperalgesia in humans.

In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation causing central sensitization.