Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

Background To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. Methods Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic–pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) – P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. Results The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. Conclusions These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Benefit versus Severe Side Effects of Opioid Analgesia

Anesthesiology ◽

10.1097/aln.0000000000002138 ◽

2018 ◽

Vol 128 (5) ◽

pp. 932-942 ◽

Cited By ~ 6

Author(s):

Margot Roozekrans ◽

Rutger van der Schrier ◽

Leon Aarts ◽

Elise Sarton ◽

Monique van Velzen ◽

...

Keyword(s):

Utility Function ◽

Respiratory Depression ◽

Opioid Analgesic ◽

Population Pharmacokinetic ◽

Analgesic Effects ◽

Effect Site ◽

Single Function ◽

Pharmacodynamic Analysis ◽

Effect Site Concentration ◽

New Compounds

Abstract Background Previous studies integrated opioid benefit and harm into one single function—the utility function—to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example. Methods Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic–pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression. Results The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression. Conclusions The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs.

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Behavioral and Physiological Effects of Remifentanil and Alfentanil in Healthy Volunteers

Anesthesiology ◽

10.1097/00000542-199903000-00013 ◽

1999 ◽

Vol 90 (3) ◽

pp. 718-726 ◽

Cited By ~ 35

Author(s):

Matthew L. Black ◽

Joanna L. Hill ◽

James P. Zacny

Keyword(s):

Healthy Volunteers ◽

Dose Range ◽

Subjective Effects ◽

Cold Pressor Test ◽

Drug Effects ◽

Cold Pressor ◽

Psychomotor Tests ◽

Potency Ratio ◽

Psychomotor Effects ◽

Double Blinded

Background The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non-drug-abusing volunteers. Alfentanil was used as a comparator drug. Methods Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo-controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions (determined with STANPUMP, a computer modeling software package) were given to achieve three predicted constant plasma levels for 40 min each of remifentanil (0.75, 1.5, and 3 ng/ml) and alfentanil (16, 32, and 64 ng/ml). Mood forms and psychomotor tests were completed, and miosis was assessed, during and after the infusions. In addition, analgesia was tested at each dose level using a cold-pressor test. Results Remifentanil had prototypic micro-like opioid subjective effects, impaired psychomotor performance, and produced analgesia. Alfentanil at the dose range tested had more mild effects on these measures, and the analgesia data indicated that a 40:1 potency ratio, rather than the 20:1 ratio we used, may exist between remifentanil and alfentanil. A psychomotor test administered 60 min after the remifentanil infusion was discontinued showed that the volunteers were still impaired, although they reported feeling no drug effects. Conclusions The notion that the pharmacodynamic effects of remifentanil are extremely short-lived after the drug is no longer administered must be questioned given our findings that psychomotor effects were still apparent 1 h after the infusion was discontinued.

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Pregabalin Has Analgesic, Ventilatory, and Cognitive Effects in Combination with Remifentanil

Anesthesiology ◽

10.1097/aln.0000000000000913 ◽

2016 ◽

Vol 124 (1) ◽

pp. 141-149 ◽

Cited By ~ 37

Author(s):

Marianne Myhre ◽

Lien My Diep ◽

Audun Stubhaug

Keyword(s):

Pain Score ◽

Cold Pressor Test ◽

Experimental Pain ◽

Cold Pressor ◽

Analgesic Effects ◽

Rapid Information Processing ◽

End Tidal ◽

Double Blinded ◽

Dose Dependent ◽

Higher Doses

Abstract Background Pregabalin is widely used perioperatively. The authors explored the effects of pregabalin, remifentanil, and their combination on experimental pain, ventilatory, and cognitive function. Methods In a randomized, double-blinded crossover study, 12 volunteers received (1) pregabalin + placebo, (2) placebo + remifentanil, (3) pregabalin + remifentanil, and (4) placebo + placebo. Pregabalin 150 mg/placebo was administered twice orally. After baseline, remifentanil/placebo was given as effect-site target-controlled infusion (TCI): 0.6, 1.2, and 2.4 ng/ml. Pain during cold pressor test was scored on visual analog scale (0 to 100 mm). Ventilation was measured by spirometry and cognition tested with Color-Word Interference and Rapid Information Processing tests. Results Pain intensity after placebo was (mean) 72 mm (95% CI, 62 to 83). Pregabalin reduced pain score by −10 mm (−14 to −7, P < 0.001). Remifentanil had dose-dependent analgesic effect, reducing pain score by −47 mm (−54 to −39, P < 0.001) on highest TCI level, whereas pregabalin + remifentanil exerted additive effect, reducing pain score by −57 mm (−64 to −50, P < 0.001). Respiratory depression was potentiated by adding pregabalin to remifentanil; end-tidal carbon dioxide was 39.3 mmHg (37.2 to 41.3) with placebo, increased 1.8 mmHg (−0.9 to 4.6, P = 0.4) with pregabalin, 10.1 mmHg (4.9 to 15.4, P < 0.001) with remifentanil, and 16.4 mmHg (11.3 to 21.5, P < 0.001) with pregabalin + remifentanil on highest TCI level. The combination pregabalin + remifentanil, but not either drug alone, adversely affected all cognitive tests. Conclusions The combination of pregabalin and remifentanil had additive analgesic effects, pregabalin potentiated remifentanil ventilatory depression, and the combination adversely affected cognition. These results question the clinical benefit of the combination compared with higher doses of opioids.

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Savor the flavor - a randomized double-blind study on taste-enhanced placebo analgesia in healthy volunteers

10.1101/2021.08.16.21262058 ◽

2021 ◽

Author(s):

Matthias Zunhammer ◽

Gerrit Goltz ◽

Maximilian Schweifel ◽

Boris A Stuck ◽

Ulrike Bingel

Keyword(s):

Healthy Volunteers ◽

Cold Water ◽

Cold Pressor Test ◽

Cold Pressor ◽

Cost Effective ◽

Double Blind Study ◽

Placebo Analgesia ◽

Double Blind ◽

Analgesic Effects ◽

Clinical Scenarios

We conducted a randomized, double-blind, between-group study to investigate how the taste of oral medication affects placebo analgesia. Over three sub-studies, 318 healthy volunteers (297 included) were subjected to experimental tonic cold water pain (cold pressor test) before and after receiving taste-neutral (water), bitter (quinine), sweet (saccharine), or no placebo drops. Pain ratings indicated that taste enhances placebo analgesia. This effect was small but accounted for a substantial portion of the overall placebo effect and was comparable to WHO stage 1 analgesic effects. Moreover, placebo treatments were associated with an increase in peak heart rate response to cold water. Adverse effects were minimal. These results indicate that added taste may be an easy-to-implement, cost-effective, and safe way to optimize treatment outcomes and that taste-neutral preparations may reduce placebo-related outcome variance in clinical trials. Further studies are needed to test if these findings can be translated into clinical scenarios.

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A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers

Journal of Psychopharmacology ◽

10.1177/0269881120940937 ◽

2020 ◽

pp. 026988112094093 ◽

Cited By ~ 3

Author(s):

Johannes G Ramaekers ◽

Nadia Hutten ◽

Natasha L Mason ◽

Patrick Dolder ◽

Eef L Theunissen ◽

...

Keyword(s):

Healthy Volunteers ◽

Pain Perception ◽

Psychiatric Symptoms ◽

Cold Pressor Test ◽

Cold Pressor ◽

Lysergic Acid ◽

Pain Tolerance ◽

Lysergic Acid Diethylamide ◽

Analgesic Effects ◽

1960S And 1970S

Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide. Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects. Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments. Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization. Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.

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Pleasant Pain Relief and Inhibitory Conditioned Pain Modulation: A Psychophysical Study

Pain Research and Management ◽

10.1155/2018/1935056 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Nathalie Bitar ◽

Serge Marchand ◽

Stéphane Potvin

Keyword(s):

Pain Relief ◽

Cold Pressor Test ◽

Cold Pressor ◽

Pain Modulation ◽

Conditioned Pain Modulation ◽

Thermal Stimulus ◽

Analgesic Effects ◽

Opponent Process ◽

Before And After ◽

Opponent Process Theory

Background. Inhibitory conditioned pain modulation (ICPM) is one of the principal endogenous pain inhibition mechanisms and is triggered by strong nociceptive stimuli. Recently, it has been shown that feelings of pleasantness are experienced after the interruption of noxious stimuli. Given that pleasant stimuli have analgesic effects, it is therefore possible that the ICPM effect is explained by the confounding effect of pleasant pain relief. The current study sought to verify this assumption. Methods. Twenty-seven healthy volunteers were recruited. Thermal pain thresholds were measured using a Peltier thermode. ICPM was then measured by administering a tonic thermal stimulus before and after a cold-pressor test (CPT). Following the readministration of the CPT, pleasant pain relief was measured for 4 minutes. According to the opponent process theory, pleasant relief should be elicited following the interruption of a noxious stimulus. Results. The interruption of the CPT induced a mean and peak pleasant pain relief of almost 40% and 70%, respectively. Pleasant pain relief did not correlate with ICPM amplitude but was positively correlated with pain level during the CPT. Finally, a negative correlation was observed between pleasant pain relief and anxiety. Discussion. Results show that the cessation of a strong nociceptive stimulus elicits potent pleasant pain relief. The lack of correlation between ICPM and pleasant pain relief suggests that the ICPM effect, as measured by sequential paradigms, is unlikely to be fully explained by a pleasant pain relief phenomenon.

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Repercussões pressóricas do frio local: a crioterapia deve ser administrada com precaução em pacientes hipertensos?

Fisioterapia Brasil ◽

10.33233/fb.v14i4.409 ◽

2016 ◽

Vol 14 (4) ◽

Author(s):

Marcelo Coertjens

Keyword(s):

Cold Pressor Test ◽

Cold Pressor ◽

Pressor Test

Introdução: A crioterapia é um recurso que diminui a temperatura corporal local com finalidades terapêuticas. Uma importante repercussão é a vasoconstrição local, que seria o desencadeador de um possível aumento na pressão arterial (PA). Entretanto, não existem trabalhos que comprovem essa suposição. Nossa hipótese é que os resultados das pesquisas de Cold Pressor Test (CPT) avaliando PA acabaram historicamente fundamentando as precauções da crioterapia em relação a pacientes hipertensos. Objetivo: Realizar uma revisão de literatura a respeito das pesquisas que sustentam a precaução da crioterapia em indivíduos hipertensos e verificar sua relação com estudos que utilizaram o CPT. Material e métodos: Trata-se de uma revisão de literatura que utilizou as bases de dados online Medline, Scielo, Lilacs e Google Acadêmico para a realização da pesquisa. Resultado: Apesar de não serem unânimes, diversas pesquisas que utilizaram o CPT encontraram significativos aumentos da atividade nervosa simpática muscular e da PA em normotensos e hipertensos, entretanto não encontramos estudos que tenham comprovado respostas significativas de PA com o uso da crioterapia, principalmente, em hipertensos. Conclusão: Não existem evidências científicas que comprovem a precaução da crioterapia em indivíduos hipertensos. Além disso, os estudos com CPT não são unânimes em relação aos aumentos pressóricos em indivíduos normotensos e hipertensos.Palavras-chave: crioterapia, hemodinâmica, hipertensão, pressão arterial.

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