|Year : 2020 | Volume
| Issue : 1 | Page : 45-52
Intravenous buprenorphine does not impair psychomotor and cognitive functioning in opioid-dependent patients using oral dextropropoxyphene: A randomized, double-blind, crossover study
Shri Gopal Goyal1, Atul Ambekar2, Raka Jain2, Manju Mehta2, Ashwani Kumar Mishra2
1 Department of Psychiatry (DIMHANS), PBM Hospital, Sardar Patel Medical College, Bikaner, Rajasthan, India
2 Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||29-Mar-2020|
|Date of Decision||16-May-2020|
|Date of Acceptance||12-Jul-2020|
|Date of Web Publication||7-Oct-2020|
Shri Gopal Goyal
Department of Psychiatry (DIMHANS), PBM Hospital, Sardar Patel Medical College, Bikaner, Rajasthan
Source of Support: None, Conflict of Interest: None
Background and Objectives: Some opioid-dependent injecting buprenorphine (BPN) users can continue to inject BPN even while using dextropropoxyphene as a treatment or as a drug of abuse. With this rationale, this study was aimed to assess the effect of injection BPN on psychomotor and cognitive functioning in opioid-dependent patients receiving oral dextropropoxyphene. Methods: This was a randomized, placebo-controlled, double-blind, crossover study, carried out in the inpatient unit of the tertiary level de-addiction facility. Twenty opioid-dependent male, current injecting drug users were given a single dose of injection of BPN (1.2 mg) or placebo, in a crossover design, 2 h after the routine morning dose of oral dextropropoxyphene at day 4 and day 6 of admission. Psychomotor and cognitive functioning was assessed with the help of standard tools (trail making – Parts A and B, digit symbol substitution test, delayed recall test, and digit span) at baseline and after 10 min, 3 h, and 6 h of injection BPN/placebo. Results: There was no significant difference in the scores on any of the tests for psychomotor and cognitive functioning at any time period after receiving either injection BPN or placebo. Conclusions: A single dose of intravenous BPN in opioid-dependent patients on oral dextropropoxyphene did not produce any significant change in psychomotor and cognitive functioning as compared to placebo.
Keywords: Buprenorphine, dextropropoxyphene, injecting drug users, opioids, psychomotor and cognitive functioning
|How to cite this article:|
Goyal SG, Ambekar A, Jain R, Mehta M, Mishra AK. Intravenous buprenorphine does not impair psychomotor and cognitive functioning in opioid-dependent patients using oral dextropropoxyphene: A randomized, double-blind, crossover study. J Mental Health Hum Behav 2020;25:45-52
|How to cite this URL:|
Goyal SG, Ambekar A, Jain R, Mehta M, Mishra AK. Intravenous buprenorphine does not impair psychomotor and cognitive functioning in opioid-dependent patients using oral dextropropoxyphene: A randomized, double-blind, crossover study. J Mental Health Hum Behav [serial online] 2020 [cited 2021 Jun 24];25:45-52. Available from: https://www.jmhhb.org/text.asp?2020/25/1/45/297415
| Introduction|| |
Drug dependence is a major problem which poses a significant burden on health care globally, including India. A major proportion of the patients seeking treatment at drug treatment services in India are opioids dependent. The propensity of opioids to impair cognitive and psychomotor functioning has been assessed through a number of individual studies, as well as review studies. Such studies address the hazards of engaging in a certain type of activities requiring higher levels of psychomotor functioning (such as driving, operating machinery, and taking care of young children), which are usual in daily life. Opioids are most widely prescribed drugs for analgesia and as maintenance agents for opioid dependence. Buprenorphine (BPN), as one of the maintenance agents, has also been studied about its potential to affect psychomotor performance in a variety of individuals. In healthy volunteers, BPN administered by different routes has been found to impair psychomotor performance on a variety of tests., However, some studies did not find any significant effect on immediate and delayed recall after 300 min. In opioid drug users, most studies have shown no significant impairment on digit symbol substitution test (DSST) and trail making (Part B).,, One study found a significant impairment on DSST. In opioid-maintained patients too, similar findings have been reported.,
Thus, it appears that BPN does impair psychomotor performance in healthy volunteers, but its psychomotor and cognitive effect on opioid drug users and opioid-maintained patients are inconclusive. Sublingual BPN is an established agent for maintenance treatment of opioid dependence in various countries including India,, particularly for the injecting drug users (IDUs). However, in its injecting form, BPN is also used as a recreational/intoxicating drug. Indeed, many IDUs in India inject BPN., Propoxyphene products were prescribed throughout the world., Oral dextropropoxyphene was very commonly prescribed agent for the treatment of opioid use disorders (including injection BPN use disorders in our center, particularly outpatient department [OPD] patients, in the dose range of 390–780 mg/day in three divided doses). Indeed, the manual developed by the Ministry of Health, Government of India, for physicians on the treatment of substance use disorders also suggested this treatment regimen. However, in the recent past, the Government of India banned all the products containing dextropropoxyphene, and hence, its usage as a treatment agent has been discontinued, though there are some voices not supporting this ban. While dextropropoxyphene was being prescribed at our center, it was possible that some injecting BPN users would continue to inject BPN even while receiving dextropropoxyphene treatment in the outpatient settings. However, there was no study conducted on this patient population till now. With this rationale, this study was aimed to assess the effect of injection BPN on psychomotor and cognitive functioning in those who were receiving dextropropoxyphene treatment.
| Methods|| |
This was a randomized, placebo-controlled, double-blind, crossover study, carried out in the inpatient unit of National Drug Dependence Treatment Centre, AIIMS, New Delhi (tertiary level drug treatment facility) between July 2008 and December 2008. The sample, chosen as per convenience, comprised 20 men, sample size were calculated based on previously published studies with the following inclusion criteria: age group of 18–35 years, opioid dependent (ICD-10 guidelines), current IDUs (i.e., history of injecting drug use at least once in the preceding 6 months), currently admitted voluntarily in our center for the treatment of opioid dependence, have been prescribed and dispensed oral dextropropoxyphene for the treatment of opioid withdrawals in the dose range of 390–780 mg/day (i.e., 6–12 capsules/day) in divided dosages from OPD for at least 3 weeks and reports having taken the prescribed drug on more than 75% of the dosing days in the past 3 weeks, able to read and write and provide informed consent for participation. The exclusion criteria were as follows: dependence on substances other than opioid (except nicotine); taking medications other than dextropropoxyphene for opioid treatment; major medical illnesses including seizure, dementia, or other neurological disorders, patients with major psychiatric illness, any disability hampering communication, and failure to comply with the study protocol.
Procedure of randomization
Five random allocation tables were prepared by a senior author (AA) who was not part of data collection using computer software. Out of five random allocation tables prepared, one was selected randomly by the pharmacist, who was requested to prepare injection before the experiment. The senior author (AA) of the study prepared a code for the order of administration of injection and kept it in an envelope, which was sealed in the presence of the pharmacist and secured by her. The pharmacist was requested to prepare injection on the 4th day of the experiment, and she would prepare injection 5–10 min before the experiment as per the code. A similar procedure was adopted on the 6th day of the experiment. Measures were taken to ensure double blinding that neither the person conducting the experiment nor the individuals were aware regarding the order of administration of injection placebo and BPN. The placebo (normal saline) was identical in appearance to the brand of BPN used, i.e., a clear liquid. This ensured no chance of identification through the color of liquid.
The ethical clearance was obtained from the institution's ethics committee.
The tools used for the study were a semi-structured questionnaire, the DSST, trail making test, digit span test, and delayed recall test. The DSST is a paper-and-pencil test that requires the participant to replace digits with corresponding symbols according to a digit-symbol code listed on top of the paper. It evaluates changes in information processing performance and the ability to concentrate. The Indian adaptation of this scale, as a subtest of the Wechsler Adult Performance Intelligence Scale, was used in the study. The test is validated in India by Pershad et al. Paper/pencil trail making test, Parts A and B of the Halstead–Reitan Neuropsychological Battery,, gives a measurement of psychomotor speed and cognitive flexibility. It involves visual scanning and tracking. Digit span test, a subtest of the Wechsler Adult Intelligence Scale-Revised, is a measure of short-term memory, attention, and concentration. Delayed recall test consists of items taken from the Wechsler Memory Scale [Table 1].
After the participant had been recruited in the study and provided written informed consent, the semi-structured questionnaire was administered, and data on demographic variables, substance use, and current treatment details were noted. The participants gave a urine sample on 2 consecutive days for screening by thin-layer chromatography (TLC) to assess the presence of psychoactive substances. During the first 3 days of the study, participants received oral dextropropoxyphene in the dose range of 390–780 mg/day in divided dosages (i.e., 6–12 capsules/day) (i.e., the same dose which they were receiving in an outpatient clinic). We assessed withdrawal symptoms daily in the morning on the Subjective and Objective Opioid Withdrawal Scale. Per protocol, the only other medication permissible was tablet zolpidem up to 20 mg at night, if required, for insomnia. Nicotine gum was prescribed for nicotine dependence to participants. On day 4, before the actual experiment, participants' urine was tested again for morphine and benzodiazepine by morphine (300) urine test (cassette) and benzodiazepine urine test (cassette), respectively, to exclude the use of any psychoactive substance during the study period. Participants were allocated randomly to either of the experimental arms – placebo or BPN – using a random table. This was done by a pharmacist, not related to the study. Normal saline was used as placebo, which was similar in appearance as an active drug.
The protocol of experiment was as follows: on day 1 of the experiment (i.e., day 4 of the study), baseline – “0” h (2 h after the routine morning dose of oral dextropropoxyphene) – recording of pulse rate, blood pressure, respiratory rate, and assessment using all the abovementioned tools was conducted. After the assessment, injection of BPN/placebo, 4 ml (i.e., 1.2 mg of BPN)), in an upper extremity vein was given and vital signs were assessed immediately after injection. (dose of BPN was decided based on clinical observation of senior authors of our study that most of the patients were abusing 2 ampoule of injection BPN [1 ampoule (2 ml) of injection BPN contains 0.6 mg of BPN]. Hence, we planned to use 1.2 mg [4 ml] dose of injection BPN in our study. Afterward, with the tools mentioned above, psychomotor and cognitive functioning was assessed at 10 min, 3, and 6 h. After a 48-h washout period for placebo/BPN, i.e., on day 3 of the experiment (i.e., day 6 of the study), baseline – “0” h (2 h after the routine morning dose of oral dextropropoxyphene) –recording of pulse rate, blood pressure, respiratory rate, and assessment on all the abovementioned tools was conducted. After the assessment, injection of BPN/placebo (crossover), 4 ml (i.e., 1.2 mg of BPN), in an upper extremity vein was given and vital signs were assessed immediately after injection. Afterward, with the tools mentioned above, psychomotor and cognitive functioning was assessed at 10 min, 3, and 6 h. The procedure is summarized in [Figure 1].
Descriptive statistical measures (mean, median, standard deviation, and range) were estimated for summarizing the quantitative characteristics related to demographic variables, drug abuse, treatment history, and scores on various instruments.
The data were analyzed by general linear model repeated measure. Since the study design was crossover, the test of within-subjects was performed by declaring the 2 × 4 combination in the repeated measure, corresponding to the two treatments (BPN and placebo). The results for the treatment and interaction effects have been summarized [Table 2]a and [Table 2]b in terms of sum of squares, the degrees of freedom, mean sum of squares, F-statistic, and the corresponding two-sided P value. Corresponding to the combination of time and treatment, various hypotheses were tested: (i) Were there significant variations from patient to patient (patients-P)? (ii) Did BPN have any effect (treatment-T)? (iii) Was the effect of BPN similar in all patients (P X T)? (iv) Were the differences between the time points significant (time-t)? (v) Were the differences between patients consistently seen at all the time points (t × p)? and (vi) Was the effect of BPN similar at all time points (t × T)?. The analysis was carried out for each of the quantitative measurements (trail making A, trail making B, DSST, digit span forward, digit span backward, digit span total, delayed recall test, trail making error A, trail making error B, and DSST). The profile plot for each of the quantitative measures at four time points across two treatments was also visualized, and it was suggestive of no interaction effect. The data were analyzed through licensed SPSS 21.0 version software (IBM Corp., Armonk, NY).
| Results|| |
The mean age of the participants and years of formal education was 28.7 ± 5.7 (range of 20–35) and 8.6 ± 2.9, respectively. Almost half of the participants were married, and the majority were currently employed. Thirteen (65%) of the twenty participants were paid workers, six participants (30%) were self-employed, and one (5%) was an unclassifiable category (pickpocketer). Nineteen (95%) of the twenty participants resided in the nuclear family and one (5%) was in the joint family. Seventeen (85%) of the twenty participants were staying in an urban area and three (15%) were in a rural area.
For all the study participants, tobacco was the first substance of use, with a mean age of onset being 15.6 ± 3.9 years. By inclusion, all participants were IDUs and majority of them reported the use of drugs through injecting route in the past 1 month. The drug use profile of the participants included in the study was comparable to that of the drug use profile of other IDUs attending our center. The mean dose of capsule dextropropoxyphene (mg/day) prescribed by the center was 542.3 ± 74.0 and the total duration of capsule dextropropoxyphene use was 55.5 days, with a range of 28–300 days. All the participants reported taking capsule dextropropoxyphene in the past 21 days [Table 3].
[Table 2]a shows the scores of the participants in the BPN and placebo groups for trail making test (Parts A and B), DSST digit span (forward, backward, and total), and delayed recall test. There was an improvement of performance at each assessment in both the groups. There was a decrease in time taken to complete trail making A and trail making B from baseline to 6 h after injection in both the groups. However, there was a decrease in number of errors from baseline to 6 h. There was an increase in number of correct responses while performing DSST in both the groups. Although the number of errors increased from baseline to 10 min but subsequently decrease in numbers of errors from 10 min to 6 h in the BPN group. However, in the placebo group, errors in this test were gradually decreased from baseline to 6 h. The number of digits recalled in digit span and delayed recall test increased from baseline to 6 h in both the groups. However, when data were compared between BPN and placebo at various time points, no significant difference was found [Table 2]a and [Figure 2], [Figure 3].
General linear model repeated measure
The repeated assessment suggested significant variations in all measures from patients to patients across all measures except DSST (error). Moreover, BPN has a significant effect on all measures except DSST (error). The effect of BPN was similar across all patients for all the parameters except the two trail making tests (trail making A and trail making A [error]). At all time points, significant variations were noted for all the parameters. The differences between patients were consistently seen at all the time points for the parameters, such as trail making A, DSST, trail making A (error), and DSST (error), but across these parameters, the effect of BPN was not similar across for all the time points (significant interaction term t × P) [Table 2]b.
The total score on the Subjective and Objective Opioid Withdrawal Scale gradually decreased from day 1 to 7. There was no significant relationship between withdrawal scale score and tests of cognitive functioning [Table 4].
| Discussion|| |
In the present study, we compared the effect of injection BPN (1.2 mg) and placebo administered in double-blind, crossover fashion in 20 male, opioid-dependent inpatients on treatment with oral dextropropoxyphene, The observation periods (i.e., baseline and at 10 min, 3 h, and 6 h after administration of the compound) were chosen to pick the peak effects of the injection BPN and to observe the changes over the passage of time. The crossover design ensured that each participant acted as its own control. The 2-day gap between both the experimental days also minimized the carryover effect of the previous injection.
We used trail making test (Parts A and B), DSST, digit span, and delayed recall test for the assessment of psychomotor and cognitive functioning. Participants' performance did not differ significantly on trail making test (Parts A and B) at any time period when either injection BPN or injection placebo was administrated although there was an improvement of performance at each assessment in both the groups. A study conducted on participants with similar clinical profile found that performance on trail making test was improved significantly with each assessment. However, Strain et al., 2000, found that BPN (4, 8, or 16 mg, sublingual) did not affect performance on trail making test (Part B) in nondependent opioid users.
A similar pattern of improved performance was noted on DSST too, which is in contrast to many previous studies in opioid-maintained patients,, and in opioid drug users., In healthy volunteers, however, DSST performance was significantly impaired by intravenous BPN in a dose-related manner even by doses as small as 0.15–0.3 mg compared to saline. Weinhold et al. also reported mild impairment on DSST in opioid abusers. However, none of the previous studies revealed improvement on this test upon the BPN administration.
The same trend was evident on digit span (forward, backward, and total) test too. Similar to our study, psychomotor performance on digit span and delayed recall was unaffected by administrating an additional dose of BPN 2 mg in BPN-maintained patients. This result is in contrast to the result of several earlier studies, using an eight-digit recall task in BPN-maintained patients, methadone-maintained patients,, and healthy volunteers (Zacny et al., 1997a; b – using “a list of 15 words”)., In another study though, digit recall task was slightly impaired by BPN in methadone-maintained patients.
One of the possible reasons for these findings could be that patients were already tolerant to opioids due to ongoing dextropropoxyphene treatment. Thus, the cross-tolerance displayed by dextropropoxyphene resulted in participants not showing any psychomotor and cognitive impairment upon administration of BPN, as compared to placebo. Hence, there was no impairment in functioning after giving an additional single dose of BPN compared to placebo.
Among limitations of the study, the same set of psychomotor tests was used in each assessment in this study, giving a scope for “practice” or the “learning effect,” though this has not been reported as a concern in earlier studies.,, Using different sets of tests (e.g., different digit-symbol codes) in each assessment might be a better way to exclude the possibility of learning. In addition, while we conducted urine screening with TLC to confirm the presence or absence of drugs as per the study protocol, we did not measure the plasma concentration of BPN and dextropropoxyphene metabolites, which could have better correlated with psychomotor performance.
This study has certain important implications. As stated earlier, dextropropoxyphene was commonly used as a treatment agent for opioid dependence in India and remains available in the illicit drug market as a drug of abuse. As the findings of the study show, additional BPN on top of dextropropoxyphene did not result in significant changes in the cognitive functions. Therefore, the patients on treatment for opioid dependence and who use injecting BPN may be prescribed dextropropoxyphene without any serious concern of cognitive impairment, thereby enhancing the menu of options available for the treatment of opioid dependence lending further credence to the arguments presented by Sharma. Even if dextropropoxyphene is not available for treatment, the study continues to be relevant since this is the first-ever documentation of an interaction between BPN and dextropropoxyphene in terms of cognitive functions.
| Conclusions|| |
An additional single dose of intravenous BPN in opioid-dependent patients on oral dextropropoxyphene did not produce any significant change in psychomotor and cognitive functioning as compared to placebo.
We are immensely grateful to late Prof. BM Tripathi for his guidance during this study. We are thankful to the Indian Council of Medical Research and AIIMS, New Delhi, for providing financial support in form thesis grant under a scheme of MS/MD thesis. We would like to thank all the patients who volunteered for the study.
This study also won the Dr. Buckshey Award in the 39th Annual Conference of the Indian Psychiatric Society-North Zone held at Ludhiana on 20–21 December 2014.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
UNODC. World Drug Report. Vienna: United Nations Office on Drugs and Crime; 2008.
Ray R. The Extent, Pattern and Trends of drug abuse in India. UNODC, Regional Office for South Asia and Ministry of Social Justice and Empowerment, Government of India; 2004.
Hanks GW, O'Neill WM, Simpson P, Wesnes K. The cognitive and psychomotor effects of opioid analgesics. II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol 1995;48:455-60.
Walker DJ, Zacny JP. Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers. Psychopharmacology (Berl) 1998;140:191-201.
Zacny JP. A review of effects of opiates on psychomotor and cognitive functioning in humans. Exp Clin Psychopharm 1995;3:432-66.
Zacny JP, Conley K, Marks S. Comparing the subjective, psychomotor and physiological effects of intravenous nalbuphine and morphine in healthy volunteers. J Pharmacol Exp Ther 1997;280:1159-69.
Jensen ML, Sjogren P, Upton RN, Foster DJ, Bonde P, Graae C, et al
. Pharmacokinetic–pharmacodynamic relationships of cognitive and psychomotor effects of intravenous buprenorphine infusion in human volunteers. Basic Clin Pharmacol Toxicol 2008;103:94-101.
Zacny JP, Conley K, Galinkin J. Comparing the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers. J Pharmacol Exp Ther 1997;282:1187-97.
Preston KL, Bigelow GE. Effects of agonist-antagonist opioids in humans trained in a hydromorphone/not hydromorphone discrimination. J Pharmacol Exp Ther 2000;295:114-24.
Jones HE, Bigelow GE, Preston KL. Assessment of opioid partial agonist activity with a three-choice hydromorphone dose-discrimination procedure. J Pharmacol Exp Ther 1999;289:1350-61.
Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl) 2000;148:374-83.
Weinhold LL, Preston KL, Farre M, Liebson IA, Bigelow G. Buprenorphine alone and in combination with naloxone in nondependent humans. Drug Alcohol Dependence 1992;30:263-74.
Preston KL, Bigelow GE, Liebson IA. Buprenorphine and naloxone alone and in combination in opioid-dependent humans. Psychopharmacology (Berl) 1988;94:484-90.
Strain EC, Preston KL, Liebson IA, Bigelow GE. Acute effects of buprenorphine, hydromorphone and naloxone in methadone-maintained volunteers. J Pharmacol Exp Ther 1992;261:985-93.
Singh RR, Ambekar A. Opioid substitution treatment in a public health setting: A collaboration between hospitals and NGOs in the Punjab. Int J Drug Policy 2012;23:170-1.
Rao R, Agrawal A, Kishore K, Ambekar A. Delivery models of opioid agonist maintenance treatment in South Asia: A good beginning. Bull World Health Organ 2013;91:150-3.
Ambekar A, Tripathi BM. Size estimation of Injecting Drug Use in Punjab and Haryana. UNAIDS: New Delhi; 2008.
Ambekar A. Association of Drug Use Pattern with vulnerability and service uptake among IDUs. New Delhi: United Nations Office on Drugs and Crime (UNODC); Regional Office for South Asia, and National AIDS Control Organisation; 2012.
Dore GM. The dangers of dextropropoxyphene. Aust N
Z J Psychiatry 1996;30:864-6.
Li Wan Po A, Zhang WY. Systematic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 1997;315:1565-71.
Lal R, editor. Pharmacotherapy of substance use disorder. In: Substance Use Disorder: Manual for Physicians. New Delhi: National Drug Dependence Treatment Centre, All India Institute of Medical Sciences; 2013. p. 65-76.
Sharma DC. India urged to reverse dextropropoxyphene ban. Lancet Oncol 2013;14:e344.
Wechsler D. The Measurement and Appraisal of Adult Intelligence. London: Williams and Wilkins; 1958.
Hindmarch I. Psychomotor functions and psychotropic drugs. Br J Clin Pharmacol 1980;10:189-9.
Ramalingaswami P. Manual of Indian Adaptation of WAIS – Performance Scale. Delhi: Mansayan; 1974.
Pershad D, Verma SK, Malhotra S, Prabhakar S. Cross-validity of the battery of cognitive test of assessment of brain damage cases. Indian J Psychol 1984;59:36-44.
Halstead WC. Brain and Intelligence. Chicago: University of Chicago Press; 1947.
Reitan RM. Investigation of the validity of Halstead's measure of biological intelligence. Arch Neurol Psychiatry 1955;73:28-35.
Wechsler D. Manual: Wechsler Adult Intelligence Scale – Revised (WAIS-R). New York Psychological Corporation; 1981.
Jain R, editor. Analytical methods. In: Detection of Drugs of Abuse in Body Fluids: A Manual for Laboratory Personnel. New Delhi: National Drug Dependence Treatment Centre, All India Institute of Medical Sciences; 1998. p. 18-44.
Singhal A, Tripathi BM, Pal HR, Jena R, Jain R. Effect of buprenorphine on psychomotor functions in patients on buprenorphine maintenance. J Opioid Manag 2008;4:41-7.
Strain EC, Walsh SL, Preston KL, Liebson IA, Bigelow GE. The effects of buprenorphine in buprenorphine-maintained volunteers. Psychopharmacology (Berl) 1997;129:329-38.
Walsh SL, Preston KL, Bigelow GE, Stitzer ML. Acute administration of buprenorphine in humans: Partial agonist and blockade effects. J Pharmacol Exp Ther 1995;274:361-72.
Zacny JP, Hill JL, Black ML, Sadeghi P. Comparing the subjective, psychomotor and physiological effects of intravenous pentazocine and morphine in normal volunteers. J Pharmacol Exp Ther 1998;286:1197-207.
Walker DJ, Zacny JP. Subjective, psychomotor and physiological effects of cumulative doses of opioid μ agonists in healthy volunteers. Psychopharmacology 1999;140:191-201.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]