In JoVE (1)
Other Publications (6)
- European Journal of Pain (London, England)
- The Journal of Pain : Official Journal of the American Pain Society
- European Journal of Pharmacology
- European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology
- British Journal of Clinical Pharmacology
- European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology
Articles by Justin L. Hay in JoVE
Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery Justin L. Hay1, Pieter Okkerse1, Guido van Amerongen1, Geert Jan Groeneveld1 1Centre for Human Drug Research (CHDR) Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy, especially when used in an integrated manner. Although implementation of these models is complex, with proper execution, the pain models described in this protocol can provide predictive and reliable results.
Other articles by Justin L. Hay on PubMed
Antinociceptive Effects of High-dose Remifentanil in Male Methadone-maintained Patients European Journal of Pain (London, England). Oct, 2008 | Pubmed ID: 18262451 The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50-110 mgday(-1)). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 microgkg(-1)min(-1), each for 2 0min. Testing was performed in the last 10 min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine-benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6+/-3.5 (mean+/-SEM)s up to 77.3+/-24.7s during this dosing protocol. During the infusion typical mu-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20-30 higher than required for the treatment of acute pain in opioid-naïve patients.
Hyperalgesia in Opioid-managed Chronic Pain and Opioid-dependent Patients The Journal of Pain : Official Journal of the American Pain Society. Mar, 2009 | Pubmed ID: 19101210 This observational study aimed to determine whether pain sensitivity in patients with noncancer chronic pain, taking either methadone or morphine, is similar to patients maintained on methadone for dependence therapy, compared with a control group. Nociceptive thresholds were measured on a single occasion with von Frey hairs, electrical stimulation, and cold pressor tests. In all subjects receiving methadone or morphine, nociceptive testing occurred just before a scheduled dose. Cold pressor tolerance values in patients with noncancer, chronic pain, treated with morphine and methadone, were 18.1 +/- 2.6 seconds (mean +/- SEM) and 19.7 +/- 2.3 seconds, respectively; in methadone-maintained subjects it was 18.9 +/- 1.9 seconds, with all values being significantly (P < .05) lower than opioid-naïve subjects (30.7 +/- 3.9 seconds). These results indicate that patients with chronic pain managed with opioids and methadone-maintained subjects are hyperalgesic when assessed by the cold pressor test but not by the electrical stimulation test. None of the groups exhibited allodynia as measured using the von Frey hairs. These results add to the growing body of evidence that chronic opioid exposure increases sensitivity to some types of pain. They also demonstrate that in humans, this hyperalgesia is not associated with allodynia.
Model of Methadone-induced Hyperalgesia in Rats and Effect of Memantine European Journal of Pharmacology. Jan, 2010 | Pubmed ID: 19818750 Methadone used for opioid dependence therapy is associated with increased pain sensitivity. This study aimed to investigate whether methadone administration lowers nociceptive threshold in adult male Sprague-Dawley (SD) rats, and if this threshold could be altered by the NMDA receptor antagonist memantine. Rats were implanted with osmotic pumps delivering 1mg/kg/day methadone (n=6), or saline placebo (n=6) (0.51 microl/h). A separate cohort of rats received either methadone 1mg/kg/day (n=8) or methadone 1mg/kg/day with 20mg/kg/day memantine (n=8). Nociception was measured by the Hargreave's paw withdrawal test. Baseline nociception was measured on day 0 prior to osmotic pump implantation and was measured daily for the following 21 days. Osmotic pumps were removed following nociceptive testing on day 14. Methadone only treated rats had a mean paw withdrawal latency significantly lower than the corresponding values for saline on days 8, 9, 10, 11, 12, 14, and 17 (P0.05). Paw withdrawal latency of rats treated with methadone co-administered with memantine did not differ significantly compared to methadone only (P>0.05). This demonstrates that methadone induces hyperalgesia in the SD rat yet this hyperalgesia resolves following discontinuation of methadone administration. Furthermore, memantine does not alter the development of methadone-induced hyperalgesia.
Dual Orexin Receptor Antagonism by Almorexant Does Not Potentiate Impairing Effects of Alcohol in Humans European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. Feb, 2013 | Pubmed ID: 22658401 The orexin system plays a pivotal role in the regulation of the sleep/wake state. Almorexant is a selective, orally available dual orexin receptor antagonist. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between almorexant (200 mg p.o.) and alcohol (0.6 g/L i.v. ethanol clamp for 5 h) using various cognitive and psychomotor performance tests in healthy subjects (n=20; 10 males and 10 females) in a 4-way crossover study. No effect of almorexant on ethanol PK was observed. The effects of ethanol on the PK of almorexant were limited, its exposure (AUC) increased by 21%; the median difference in tmax was 1.2 h; t1/2 and Cmax of almorexant were unchanged. Almorexant showed decreases in adaptive tracking performance, saccadic peak velocity, and subjective alertness as assessed by visual analog scale (VAS) of Bond and Lader, but had no or small effects on smooth pursuit eye movements, body sway, VAS for alcohol intoxication, and a memory test. Almorexant administered together with ethanol showed additive effects for adaptive tracking performance, saccadic peak velocity, subjective alertness and, possibly, calmness, but not on body sway, smooth pursuit, VAS for alcohol intoxication, or memory testing. To conclude, administration of almorexant together with ethanol was associated with additive effects for some of the measured cognitive and psychomotor performance tests. No indications of synergistic effects of almorexant and ethanol for any measured variable were observed.
Pharmacokinetics and Central Nervous System Effects of the Novel Dual NK1 /NK3 Receptor Antagonist GSK1144814 in Alcohol-intoxicated Volunteers British Journal of Clinical Pharmacology. May, 2013 | Pubmed ID: 23067311 Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated.
Pharmacokinetic and Pharmacodynamic Interactions Between Almorexant, a Dual Orexin Receptor Antagonist, and Desipramine European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology. Aug, 2014 | Pubmed ID: 24880753 Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.