The role of human drug self-administration procedures in the development of medications.

The purpose of this review is to illustrate the utility and value of employing human self-administration procedures in medication development, including abuse liability assessments of novel medications and evaluation of potential pharmacotherapies for substance use disorders. Traditionally, human abuse liability testing has relied primarily on subjective reports describing drug action by use of questionnaires; similarly, drug interactions between putative treatment agents and the drugs of abuse have relied on these measures. Subjective reports are highly valued because they provide qualitative and quantitative information about the characteristics of central and peripheral pharmacodynamic effects as well as safety and tolerability. However, self-administration procedures directly examine the behavior of interest-that is, drug taking. The present paper (1) reviews the most commonly used human self-administration procedures, (2) discusses the concordance of subjective reports and self-administration within the context of medications development for substance use disorders, focusing primarily on illustrative examples from development efforts with opioid and cocaine dependence, and (3) explores the utility of applying self-administration procedures to assess the abuse liability of novel compounds, including "abuse-deterrent" formulations (ADFs). The review will focus on opioid and cocaine dependence because a rich database from both clinical laboratory and clinical trial research exists for these two drug classes. The data reviewed suggest that drug-induced changes in self-administration and subjective effects are not always concordant. Therefore, assessment of self-administration in combination with subjective effects provides a more comprehensive picture that may have improved predictive validity for translating to the clinical setting.

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide in healthy volunteers.

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide (N(2)O) was studied across five sessions. Twelve volunteers with no history of drug dependence sampled 30% N(2)O and 100% oxygen for 10 min each, then chose nine times, once every 5 min, among N(2)O (e.g. "Agent A"), oxygen (e.g. "Agent B"), or "drug-free air." Choice varied across subjects but was stable within subjects. Quantitative differences in subjective effects occurred within and across subjects. Some subjective effects were correlated with choice and/or differed between subjects who were consistent choosers of N(2)O versus those who were not. However, drug liking and euphoria, two face-valid measures of abuse liability, were unrelated to choice. Thus, the present study found individual differences (i.e. between-subject variability) in subjective and reinforcing effects of N(2)O and, in terms of within-subject variability, suggested that subjective effects fluctuate across sessions to a relatively greater extent than do reinforcing effects. The varying degrees of correlation between N(2)O choice and its subjective effects emphasize the need for obtaining multiple measures when characterizing abuse liability of this drug.

Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers.

RATIONALE: Conducting complete dose-response evaluations of multiple drugs in a single within-subjects experiment is very time-consuming when a complete session is required for evaluation of each dose. OBJECTIVE: To evaluate a within-session cumulative-dosing procedure as a potentially efficient method for conducting dose-response evaluations of mixed-action opioids. METHODS: Fifteen healthy volunteers received intravenous injections of saline, butorphanol, nalbuphine, pentazocine, or morphine in a randomized, double-blind, crossover design. Subjects received one injection per hour for the first 4 h, and a 3-h recovery period followed. Saline was injected first, then saline or increasing doses of each drug (except pentazocine, see below) were administered every hour for the next 3 h. The absolute doses per injection were morphine and nalbuphine 2.5, 5, and 10 mg/70 kg, butorphanol 0.5, 1, and 2 mg/70 kg, and pentazocine 7.5, 15, and 0 mg/70 kg. (The highest dose of pentazocine was omitted because of the risk of dysphoria and psychotomimesis). These injections resulted in cumulative doses of morphine or nalbuphine 2.5, 7.5, and 17.5 mg/70 kg, butorphanol 0.5, 1.5, and 3.5 mg/70 kg, and pentazocine 7.5 and 22.5 mg/70 kg. Mood, psychomotor performance, and vital signs were assessed. RESULTS: Effects of all opioids were similar, with some exceptions. Butorphanol had the strongest effects on psychomotor performance and some subjective effects. Morphine was associated with delayed or prolonged side effects. CONCLUSIONS: Orderly dose-response functions and replication of results of single-dosing studies confirmed that the cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects.

Morphine responses in humans: a retrospective analysis of sex differences.

There is increasing evidence that sex modulates the effects of opioid analgesics in nonhumans, but few studies have examined this issue in humans. Over the past seven years we have conducted several studies in which the subjective, psychomotor, and physiological effects of intravenous morphine were examined in healthy volunteers. In a retrospective analysis encompassing six studies, we re-examined the effects of 10 mg/70 kg (iv) morphine in 57 males and 27 females. There were some differences in morphine's subjective effects as a function of sex. Females reported higher ratings of 'coasting (spaced out),' 'heavy or sluggish feeling' and 'dry mouth.' No differences in degree of psychomotor impairment or physiological effects (miosis and respiration rate) of morphine emerged between males and females. Future studies should focus on other doses of morphine and other opioid drugs, assess multiple behavioral and physiological endpoints, and look at different subsamples of humans (e.g. opioid abusers).

Lack of effects of ethanol pretreatment on the abuse liability of nitrous oxide in light and moderate drinkers.

AIMS: To determine effects of ethanol-use history and ethanol pretreatment on abuse liability of nitrous oxide (N(2)O). DESIGN: Placebo-controlled, double-blind, cross-over design evaluating effects of N(2)O, 0% (100% O(2), placebo) and 30% (in O(2)), in the presence of three doses of ethanol: 0 g/kg (placebo), 0.35 g/kg and 0.7 g/kg. SETTING: Subjects sat in a reclining chair in a hospital laboratory. PARTICIPANTS: Eight healthy light drinkers (one drink or less/week) and eight healthy moderate drinkers (seven or more drinks/week) with no history of drug dependence completed the study. INTERVENTION: On three sessions (1, 3, 5) subjects drank a beverage that contained one of the three ethanol doses, then sampled for 10 minute each 0% and 30% N(2)O. During choice sessions (2, 4, 6), subjects received the same ethanol dose as in the previous session, then chose six times, once every 5 min, between 0% and 30% N(2)O. MEASUREMENTS: Subjective (self-reported) drug effects, reinforcing effects of N(2)O as assessed by choice, and psychomotor effects were measured. FINDINGS: Choice of N(2)O did not differ between light (mean = 3.4 choices) and moderate (mean = 3.2 choices) drinkers and was not influenced by ethanol dose (0 g/kg: 3.3 choices, 0.35 g/kg: 3.5 choices, 0.7 g/kg: 3.1 choices). Subjective effects of N(2)O also did not depend on ethanol-use history or ethanol dose. N(2)O liking and desire to inhale the drug again were positively correlated with N(2)O choice. CONCLUSIONS: Ethanol pretreatment and ethanol-use history had no effect on the abuse liability of N(2)O as assessed in the present study.

Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers.

RATIONALE: The psychopharmacological profile of hydromorphone, an opioid that has been used extensively for many years for post-operative pain management, has not been adequately characterized in non-drug abusers. OBJECTIVES: To characterize the subjective, psychomotor, and physiological effects of a range of single doses of hydromorphone in non-drug-abusing volunteers and to compare the effects of hydromorphone with that of morphine, a benchmark mu opioid agonist. METHODS: Subjects in a six-session study were injected in an upper extremity vein with 0, 0.33, 0.65, 1.3 mg/70 kg hydromorphone, and 5 and 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. RESULTS: Hydromorphone increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of ("dry mouth", "flushing", and "nodding", and increased visual analog scale ratings indicative of both pleasant (e.g., drug liking) and unpleasant (e.g., "feel bad") effects. The subjective effects of morphine at putatively equianalgesic doses to those of hydromorphone were similar to those of hydromorphone, but in some cases of lesser magnitude. Psychomotor impairment was modest with hydromorphone and absent with morphine. Both opioids produced dose-dependent decreases in pupil size. A relative potency analysis indicated that hydromorphone was 10 times as potent as morphine (1 mg hydromorphone=10 mg morphine). CONCLUSIONS: The results of this study demonstrate that 0.33-1.3 mg hydromorphone had orderly, dose-related effects on subjective, psychomotor, and physiological variables, and similar effects to those of a benchmark mu opioid agonist, morphine.

The effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in healthy volunteers.

UNLABELLED: We studied the effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in human volunteers. We hypothesized that nitrous oxide and sevoflurane would produce both opposing and potentiating effects within the same study. Over the course of three sessions, 20 subjects inhaled 0%, 0.2%, or 0.4% end-tidal sevoflurane for a 68-min period that was divided into four 17-min blocks. During either the second or fourth block, 30% end-tidal nitrous oxide was added to the concentration of sevoflurane being inhaled. Pain response, psychomotor performance, and mood were evaluated during the second and fourth blocks. Pain ratings were higher when sevoflurane and nitrous oxide were administered together than when nitrous oxide was administered alone, which indicates that sevoflurane attenuated the analgesic effects of nitrous oxide. Sevoflurane increased self-reported ratings of sleepiness, and the addition of nitrous oxide decreased these ratings. Nitrous oxide potentiated psychomotor impairment that was induced by sevoflurane. The combination of sevoflurane and nitrous oxide produced both opposing and potentiating effects within the same study. The results suggest that nitrous oxide and sevoflurane may act through different neurochemical mechanisms on some end points, such as analgesia and sleepiness. IMPLICATIONS: Healthy volunteers inhaled subanesthetic concentrations of sevoflurane and nitrous oxide. Sevoflurane made nitrous oxide less effective as an analgesic, and nitrous oxide made sevoflurane less effective as a sedative. The two drugs may work at cross purposes on different end points of anesthesia.

Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers.

The subjective, psychomotor, and physiological effects of three opioid mu-receptor agonists were studied in healthy volunteers using a cumulative-dosing procedure. Sixteen volunteers with no history of drug abuse received i.v. injections of saline (SAL), morphine (MOR), hydromorphone (HM), or meperidine (MEP) in a randomized double-blind crossover design. Subjects received 1 injection/h for the first 4 h, and a 3-h recovery period followed. SAL was injected first during each session, then SAL or increasing doses of each drug were administered every hour for the next 3 h. The absolute doses per injection were MOR: 2.5, 5, and 10 mg/70 kg; HM: 0.33, 0.65, and 1.3 mg/70 kg; and MEP: 17.5, 35, and 70 mg/70 kg. These injections resulted in cumulative doses of MOR: 2.5, 7.5, and 17.5; HM: 0.33, 0.98, and 2.28; and MEP: 17.5, 52.5, and 122.5 mg/70 kg. Subjects completed mood forms and psychomotor tests, and physiological measures were recorded at various times after each injection and during recovery. MEP tended to produce the most intense effects immediately after drug injection, which dissipated rapidly. MOR produced the mildest effects but was associated with unpleasant side effects during recovery and after the session. HM's effects were stronger than MOR's, and the recovery from HM was slower than with MEP. None of the opioids produced consistent effects that are typically associated with abuse liability. Orderly dose-response functions suggested that our cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects within the same study.

Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers.

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.

Reinforcing, subjective, and psychomotor effects of sevoflurane and nitrous oxide in moderate-drinking healthy volunteers.

AIMS: To characterize the reinforcing, subjective and psychomotor effects of sevoflurane, a volatile anesthetic, across a range of subanesthetic concentrations in non-drug-abusing humans. In addition, a concentration of nitrous oxide was included in the design in order to compare and contrast behavioral effects of a gaseous to a volatile anesthesic. DESIGN: Repeated measures, double-blind, placebo control experiment. SETTING: Human psychopharmacology laboratory. PARTICIPANTS: Fourteen moderate-drinking healthy volunteers. INTERVENTION: In each of four sessions, subjects first sampled placebo-oxygen and an active drug (end-tidal concentrations of 0.2, 0.4, 0.6% sevoflurane and 30% nitrous oxide in oxygen) and then chose between the two MEASUREMENTS: Mood and psychomotor performance during the sampling trials, and choice of drug or placebo-oxygen during choice trial. FINDINGS: Nitrous oxide was chosen by 71% of the subjects, and 0.2, 0.4 and 0.6% sevoflurane were chosen by 50%, 57% and 50% of the subjects, respectively. Neither drug was chosen at levels that exceeded that of chance. Sevoflurane and nitrous oxide both impaired psychomotor performance and produced changes in mood. There were several differences in subjective effects between sevoflurane and nitrous oxide at concentrations which were considered to be equivalent in anesthetic effect. Finally, although sevoflurane did not function as a reinforcer in the majority of individuals tested, there was evidence that sevoflurane functioned as a reinforcer in some volunteers: subjects who chose to inhale sevoflurane over placebo-oxygen tended to report a positive spectrum of subjective effects during the sevoflurane sampling trial, relative to those subjects who chose placebo-oxygen over sevoflurane. CONCLUSIONS: Although sevoflurane did not function as a reinforcer in the majority of subjects tested, the correspondence between positive subjective effects of sevoflurane and subsequent sevoflurane choice suggests that the volatile anesthetic drug can function as a reinforcer in some moderate drinkers.

Anesthesia is a risk factor for drug and alcohol craving and relapse in ex-abusers.

Relapse to cocaine, heroin, and alcohol is a common occurrence in ex-abusers of these substances. Although there are many potential causes for relapse, we postulate that one cause in some people may be re-exposure in an anesthesia setting to a drug similar to the formerly abused drug. We hypothesize, for example, that opioids given during and after surgery may reinstate craving for, and initiate subsequent seeking of, heroin in former abusers. There are a substantial number of animal studies and some human studies documenting a reinstatement phenomenon in which an experimenter-administered psychoactive drug can precipitate drug-seeking behavior in 'abstinent' animals and humans. There is concern amongst health professionals and patients alike on this issue, and we discuss possible avenues of research, both preclinical and clinical, to explore the validity of our hypothesis.

Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers.

The subjective, psychomotor, and physiological effects of analgesic doses of oral codeine and morphine were examined in 12 healthy volunteers. Subjects ingested placebo, morphine 20 or 40 mg, or codeine 60 or 120 mg in a randomized, double-blind, crossover design. The smaller and larger doses of each drug were putatively equianalgesic, and the cold-pressor test was included to test this assumption. Codeine and morphine increased ratings of "feel drug effect" but had little effect on other subjective measures, including the Addiction Research Center Inventory, visual analog scales, and adjective checklists. The few subjective effects that were observed were modest and were dose-related for morphine but not for codeine. The drugs did not affect performance on Maddox-Wing, digit-symbol substitution, coordination, auditory reaction, reasoning, and memory tests. Dose-related decreases in pupil size (miosis) were observed following codeine and morphine. Ratings of pain intensity decreased in a dose-related manner for morphine but not for codeine. Plasma codeine and morphine levels varied as an orderly function of dose. These results suggest that oral codeine and morphine are appropriate drugs for outpatient pain relief because they are effective analgesics at doses that have only modest effects on mood, produce few side effects, and do not impair performance. The results also suggest a possible ceiling effect of codeine on analgesia and subjective effects.

Effects of ethanol and nitrous oxide, alone and in combination, on mood, psychomotor performance and pain reports in healthy volunteers.

Ethanol and nitrous oxide (N2O) are sometimes used in combination by recreational drug users. The subjective effects of this drug combination have not been examined, and was the basis for the present study. The effects of both drugs were examined alone and in combination. Dependent measures included mood, cognitive/psychomotor performance, and pain reports. Volunteers (N = 11) first consumed a drink containing ethanol (0, 0.25, or 0.5 g/kg), waited for 15 min, and then inhaled 100% oxygen (placebo) or 30% N2O in oxygen for 35 min. Thirty minutes into the inhalation, subjects immersed their non-dominant forearm in icy water for 3 min. Ethanol increased ratings of 'feel drug effect' and 'drunk'. N2O affected several mood ratings, impaired cognitive/psychomotor performance, and reduced pain reports. There were several instances of ethanol potentiating the effects of N2O, and instances in which the drug combination produced effects that neither drug alone did. Ethanol did not potentiate the analgesic effects of N2O. Overall, the data obtained in the study did not convincingly demonstrate that the drug combination of N2O and ethanol had a greater abuse liability than did N2O alone, at the doses that were tested.

Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of pentazocine in non-drug-abusing volunteers and to compare and contrast the effects of pentazocine with those of morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 7.5, 15 or 30 mg/70 kg pentazocine or 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. Pentazocine increased scores on the pentobarbital-chlorpromazine-alcohol group and lysergic acid diethylamide scales and decreased scores on the benzedrine group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "sweating" and "turning of stomach" and increased visual analog scale ratings of "difficulty concentrating," "drunk" and "having unpleasant bodily sensations." Pentazocine (30 mg) had a greater propensity to increase ratings associated with dysphoria than did 10 mg of morphine. Pentazocine produced impairment on four measures of psychomotor performance. Ten milligrams of morphine produced minimal psychomotor impairment. Both pentazocine and morphine induced miosis, but 10 mg of morphine had a greater magnitude of effect than 30 mg of pentazocine. The results of the present study demonstrate that 7.5 to 30 mg of pentazocine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of pentazocine, 30 mg, produced a greater magnitude of dysphoric subjective effects than did 10 mg of morphine, which is consistent with the literature reporting that pentazocine has a greater likelihood of inducing psychotomimesis than do other opioids.

Effects of information on the reinforcing, subjective, and psychomotor effects of nitrous oxide in healthy volunteers.

The purpose of this study was to characterize the reinforcing, subjective, and psychomotor effects of nitrous oxide (N2O) in healthy volunteers who were given different amounts of information regarding the drugs they were being administered in the experiment. A choice procedure was used in which subjects first sampled a placebo and a given concentration of N2O and then chose between the two. N2O concentration varied across the four-session experiment from 10-40%. Besides choice, subjective and psychomotor effects served as dependent measures. In the INFORMED group (n = 11), subjects were told at the beginning of each sampling trial what concentration of N2O they were inhaling or whether they were inhaling 100% oxygen (placebo). They were also informed about the prototypic effects of N2O (e.g. tingling or numbing, euphoria, dysphoria) and oxygen (e.g. no discernible effects). In the NON-INFORMED group (n = 11), subjects were only told at the beginning of each sampling trial that the drugs they would be inhaling came from one of six classes of drugs. Thirty percent N2O was chosen by a significantly higher proportion of subjects than expected by chance in the INFORMED group, but not in the NON-INFORMED group. Further, the probability of choosing 20-40% N2O was higher in the INFORMED group than in the NON-INFORMED group. Subjective effects of N2O were not affected by the information manipulation. Psychomotor performance at the highest N2O concentration tested (40%) was impaired to a greater extent in the NON-INFORMED than in the INFORMED group. We conclude that the reinforcing effects of N2O, and perhaps the impairing effects, can be modulated by telling subjects beforehand that they are inhaling N2O and what effects they might be expected to experience from the drug.

Subjective, psychomotor, cognitive, and analgesic effects of subanesthetic concentrations of sevoflurane and nitrous oxide.

BACKGROUND: Sevoflurane is a volatile general anesthetic that differs in chemical nature from the gaseous anesthetic nitrous oxide. In a controlled laboratory setting, the authors characterized the subjective, psychomotor, and analgesic effects of sevoflurane and nitrous oxide at two equal minimum alveolar subanesthetic concentrations. METHODS: A crossover design was used to test the effects of two end-tidal concentrations of sevoflurane (0.3% and 0.60%), two end-tidal concentrations of nitrous oxide (15% and 30%) that were equal in minimum alveolar concentration to that of sevoflurane, and placebo (100% oxygen) in 12 healthy volunteers. The volunteers inhaled one of these concentrations of sevoflurane, nitrous oxide, or placebo for 35 min. Dependent measures included subjective, psychomotor, and physiologic effects, and pain ratings measured during a cold-water test. RESULTS: Sevoflurane produced a greater degree of amnesia, psychomotor impairment, and drowsiness than did equal minimum alveolar concentrations of nitrous oxide. Recovery from sevoflurane and nitrous oxide effects was rapid. Nitrous oxide but not sevoflurane had analgesic effects. CONCLUSIONS: Sevoflurane and nitrous oxide produced different profiles of subjective, behavioral, and cognitive effects, with sevoflurane, in general, producing an overall greater magnitude of effect. The differences in effects between sevoflurane and nitrous oxide are consistent with the differences in their chemical nature and putative mechanisms of action.

Comparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of buprenorphine in nondrug-abusing volunteers and to compare and contrast the effects of equianalgesic doses of buprenorphine and morphine. Sixteen subjects without histories of opiate dependence were injected in an upper extremity vein with 0, 0.075, 0.15 or 0.3 mg/70 kg buprenorphine, or 10 mg/70 kg morphine, using a randomized, double-blind, cross-over design. The 0.3-mg buprenorphine dose and 10-mg morphine dose are considered to be equianalgesic and are doses commonly given for relief of postoperative pain. Buprenorphine increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and decreased scores on the Benzedrine Group scale of the Addiction Research Center Inventory, increased adjective checklist ratings of "nodding," "skin itchy," and "turning of stomach," and increased visual analogue scale ratings of "dizzy," "nauseous" and "sleepy." Buprenorphine (0.3 mg) in general had subjective effects of greater magnitude than that of 10 mg morphine. Buprenorphine produced impairment on five measures of psychomotor performance in a dose-related fashion. Ten mg morphine produced minimal psychomotor impairment. Both buprenorphine and morphine induced miosis, but buprenorphine (0.3 mg) had a larger and longer effect than that of 10 mg morphine. Buprenorphine, but not morphine, decreased respiration rate. The results of our study demonstrate that 0.075 to 0.3 mg buprenorphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. Further, a clinically relevant dose of buprenorphine, 0.3 mg, produced a greater magnitude of subjective and psychomotor-impairing effects than did an equianalgesic dose of morphine.

The influence of three L-type calcium channel blockers on morphine effects in healthy volunteers.

UNLABELLED: Numerous animal studies and several clinical studies have shown that calcium channel blockers (CCBs) augment opioid analgesia. We sought to determine whether three CCBs from three L-type subgroups (i.e., L-CCBs) enhanced morphine analgesic effects in healthy volunteers, and whether other effects of morphine (e.g., mood-altering effects) were altered by the CCB pretreatment. We examined the effects of three L-CCBs--diltiazem (30 mg, per os [P.O.]), nimodipine (60 mg, P.O.), and verapamil (80 mg, P.O.)--on morphine (10 mg/70 kg, intravenously) effects in nine healthy volunteers. Subjects first ingested the oral drug or placebo and 120 min later were injected with morphine or saline. Dependent measures included pain ratings measured during a cold-pressor test and subjective, psychomotor, and physiological effects. The L-CCBs alone had no effect on any of the dependent measures. Morphine alone and in combination with the L-CCBs reduced pain ratings, but there were no statistically significant differences in the pain measures between the morphine alone and the L-CCB/morphine conditions. Pretreatment with the L-CCBs in most cases neither potentiated nor attenuated the other effects of morphine. L-CCBs as well as the N-type CCBs currently under drug development should continue to be investigated to determine their potential as analgesic adjuvants. IMPLICATIONS: This study is important because the results are at odds with numerous animal studies and several clinical studies, which indicate that calcium channel blockers of the L-type increase the amount of analgesia produced by morphine. Using clinically relevant doses of L-type blockers, we could find no potentiation of morphine analgesia.