Pain models in animals have shown low predictivity for analgesic efficacy in humans, and clinical studies are often very confounded, blurring the evaluation. Human experimental pain models may therefore help to evaluate mechanisms and effect of analgesics and bridge findings from basic studies to the clinic. The present review outlines the concept and limitations of human experimental pain models and addresses analgesic efficacy in healthy volunteers and patients. Experimental models to evoke pain and hyperalgesia are available for most tissues. In healthy volunteers, the effect of acetaminophen is difficult to detect unless neurophysiological methods are used, whereas the effect of nonsteroidal anti-inflammatory drugs could be detected in most models. Anticonvulsants and antidepressants are sensitive in several models, particularly in models inducing hyperalgesia. For opioids, tonic pain with high intensity is attenuated more than short-lasting pain and nonpainful sensations. Fewer studies were performed in patients. In general, the sensitivity to analgesics is better in patients than in healthy volunteers, but the lower number of studies may bias the results. Experimental models have variable reliability, and validity shall be interpreted with caution. Models including deep, tonic pain and hyperalgesia are better to predict the effects of analgesics. Assessment with neurophysiologic methods and imaging is valuable as a supplement to psychophysical methods and can increase sensitivity. The models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. Knowledge obtained from this review can help design experimental pain studies for new compounds entering phase I and II clinical trials.

Human Experimental Pain Models for Assessing the Therapeutic Efficacy of Analgesic Drugs

Opioids and abnormal pain perception: New evidence from a study of chronic opioid addicts and healthy subjects.

AIM
Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.2009.03456.x

Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review

BACKGROUND: Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. METHODS: The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. RESULTS: Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. CONCLUSIONS: Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone.

Endogenous opiates and behavior: 2004

Aims

The coadministration of subantinociceptive doses of oxycodone with morphine has recently been shown to result in a synergistic antinociceptive effect in rats. The present study was aimed to investigate the possibility that coadministration of morphine and oxycodone can produce a similar synergistic effect in humans exposed to an experimental model of cold pressor test (CPT).



Methods

The enriched enrolment design was used to exclude ‘stoic’ and ‘placebo responders’ in a single-blind fashion. ‘Nonstoic’, placebo ‘nonresponder’ female volunteers (n = 30) were randomly assigned to receive 0.5 mg kg−1 oral morphine sulphate, 0.5 mg kg−1 oral oxycodone hydrochloride, and the combination of 0.25 mg kg−1 morphine sulphate with 0.25 mg kg−1 oxycodone hydrochloride, 1 week apart from each other, in a double-blind crossover design. Latency to pain onset (threshold), pain intensity (VAS), and pain tolerance (time until removal of the hand from the water) were measured six times over a 3-h period, subsequent to the administration of each medication, and were used to assess their antinociceptive effect.



Results

The combination produced a significantly higher effect on latency to pain onset than that of morphine alone [difference in mean postbaseline value 2.2; 95% confidence interval (CI) 0.48, 3.9; P = 0.01] but the effect was nonsignificantly smaller that that of oxycodone alone. Similarly, the effect of the combination on pain tolerance was significantly larger than that of morphine alone (combination difference 8.4; 95% CI 2.5, 14.3; P = 0.007), whereas oxycodone alone caused a nonsignificantly larger effect than that of the combination treatment. Comparisons of pain magnitude failed to show any significant differences between the three treatments.



Conclusions

These results indicate that at the doses tested, morphine and oxycodone do not produce synergistic antinociceptive effects in healthy humans exposed to the CPT.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.2004.02141.x

Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study.

We thank Drs Smith and de la Iglesia for their thoughtful comments and for providing the important information generated by transforming the cold pressor test tolerance data regarding the efficacy of different morphine doses [1] into a percentage of the maximum possible response.

Several aspects of Smith and de la Iglesia's approach deserve special attention. First, a significant discrepancy between animals and humans regarding the dosage needed to produce a morphine/oxycodone synergistic effect emerges from the data presented in their letter. While the doses used in the rats [2] were subantinociceptive (producing levels of antinociception similar to those produced by saline), in the human study [3] the mean daily rescue dose of morphine and the mean constant dose of oxycodone were clearly within the clinical antinociceptive range. Second, we are not aware of any published data regarding the ED50 doses of oxycodone and morphine, either alone or in combination, required for reducing cancer pain. Yet, according to Lauretti et al. [3], a synergistic effect between the two drugs was apparent during the first week of oxycodone treatment, when the mean morphine/oxycodone doses were l0 mg and 40 mg, respectively, as well as during the last week of oxycodone treatment, when the respective morphine/oxycodone doses were 10 mg and 70 mg. Until published, one can only wonder what opioid dosages were administered in the osteoarthritis studies and upon what basis. Thus, in contrast to Smith and de la Iglesia's view, it seems that the morphine/oxycodone synergy in humans may not necessarily require precise dosing. Third, it is true that we did not conduct preliminary dose-response experiments. We therefore used dosages that were based on published literature [1], as well as on what seemed to us like a clinically relevant range of doses. Fourth, we wish to emphasize the clear conclusion of our study [4], according to which the results refer only to the tested doses of opioids and to the specific experimental conditions used in the study. We purposefully avoided extrapolating these findings to any clinical conditions. Fifth, the currently available clinical trials may suggest a possible synergistic effect of the two drugs in cancer patients and perhaps in osteoarthritic patients. A naive reader may misinterpret Smith and de la Inglesia's suggestion that ‘morphine: oxycodone combinations produce greater than additive (and likely synergistic) pain relief in patients’ by generalizing such a conclusion to additional pain populations that have never actually been studied in this context. May we therefore suggest that this conclusion be modified accordingly. Lastly, we disagree in part with Smith and de la Inglesia's statement regarding the questionable suitability of the cold pressor test ‘to predict clinical relevant doses of opioids.’ It is true that all tested doses in our study produced only a minimal effect on the magnitude of pain evoked by the cold stimulation. However, the clinically relevant dose of 0.5 mg kg−1 of oral morphine increased the latency to pain onset by 47% compared to baseline, and the maximal increase produced by an equal dose of oxycodone was 120%. These magnitudes of effect are by all means large enough for the study of clinical conditions such as thermal hyperalgesia.

/pdf/response-to-smith-mt-and-de-la-iglesia-fa-coadministration-30ttrjikws.pdf

Wattan Massalha

Papers

Can coadministration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study.

Response to Smith MT and de la Iglesia FA: ‘Coadministration of oxycodone and morphine and analgesic synergy re‐examined.’