- Email: [email protected]
Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine
Drug and Alcohol Dependence 69 (2003) 317 /322 www.elsevier.com/locate/drugalcdep
Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine Olga V. Lopatko a,*, Jason M. White a, Alice Huber b, Walter Ling b a
Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide 5005, SA, Australia b UCLA Integrated Substance Abuse Programs, Los Angeles, CA 90025, USA Received 1 October 2001; accepted 10 October 2002
Abstract In maintenance patients methadone has been shown to produce considerable changes in opioid effects and withdrawal over the dosing interval. As a partial agonist buprenorphine may be expected to produce smaller changes, but the nature and magnitude of these changes have only been described for single doses. In the present study opioid effects and withdrawal were described in patients maintained on buprenorphine. Twenty four opioid dependent subjects were administered 16 mg buprenorphine tablets sublingually for 10 days. On day 10 plasma samples were collected and physiological, subjective and observer-rated measures collected pre-dose and at 14 time points during the dosing interval. No significant respiratory depression was observed. Consistent with the partial agonist properties of buprenorphine, other physiological and subjective changes were also of small magnitude. However, even at a once daily dose of 16 mg some patients experienced significant opioid withdrawal that was maximal at the end of the dosing interval. Buprenorphine maintenance should be associated with a high level of safety and a low level of disruption caused by changing opioid effects over the dosing interval, but some patients may require high doses or other strategies to completely suppress withdrawal. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Buprenorphine; Pharmacodynamics; Addiction; Maintenance
1. Introduction Methadone maintenance is effective in suppressing opioid withdrawal and achieving a range of positive health outcomes in heroin users. A major goal of methadone maintenance is to reduce the fluctuation in opioid effect and opioid withdrawal associated with administration of a short-acting opioid such as heroin. Nevertheless, examination of methadone pharmacodynamics at steady state shows significant opioid effects (e.g. pupil constriction, reduced respiration rate) that are related to changes in methadone concentration over the dosing interval (Dyer et al., 1999). In addition, significant opioid withdrawal is experienced by a subpopulation of patients (Dyer and White, 1997). This is
* Corresponding author. Tel.: /61-88-303-5989 E-mail addresses: [email protected] (O.V. Lopatko), [email protected] (J.M. White), [email protected] (W. Ling).
associated with mood disturbances (Dyer et al., 2001) and is maximal at the time of trough methadone concentration (Dyer et al., 1999). The occurrence of such withdrawal seems unrelated to absolute plasma methadone concentration (Dyer et al., 1999). Buprenorphine is a partial mu-opioid receptor agonist that has been shown to be as effective as methadone in opioid dependence treatment (Johnson et al., 2000). As a partial agonist it produces lower peak effects and milder physical dependence than full agonists such as methadone (Jasinski et al., 1978). As a result, it has greater safety and less abuse potential than methadone, but is effective in blocking both the euphoria and withdrawal produced by other opioids. The pharmacokinetic properties of buprenorphine and the relative safety of high doses allow it to be administered once daily, or, in a significant number of patients, every two, three or even 4 days (Bickel et al., 1999). Individual differences in buprenorphine effectiveness at steady state have not been reported so it is not known whether there
03765-8716/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 3 7 6 - 8 7 1 6 ( 0 2 ) 0 0 3 2 2 - 8
318
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
is a subset of patients who experience significant withdrawal towards the end of the dosing interval. To date the relationship between pharmacodynamic and pharmacokinetic parameters of buprenorphine have been reported only for single doses of the drug in both animal (Ohtani et al., 1995) and human (McQuay et al., 1980; Bullingham et al., 1980; Walsh et al., 1994) studies. In healthy male volunteers given a range of doses of buprenorphine sublingually (as solution), Walsh et al. (1994) observed a plateau for the effects of buprenorphine on subjective measures and respiratory depression. If this is true in the chronic dosing situation then it would be expected that opioid effects would show relatively little fluctuation over the buprenorphine dosing interval. To date, there are no published data relevant to this issue. The purpose of the present study was to describe the changes in opioid effects and opioid withdrawal that occur over a 24 h dosing in opioid dependent patients maintained on buprenorphine. In comparison with full agonists such as methadone, the partial agonist buprenorphine would be expected to produce relatively smaller peak opioid effects at doses that are effective in reducing withdrawal. Individual differences in withdrawal severity were also examined. The subjects in this study were administered buprenorphine (16 mg in tablet form) for a period of 10 days to allow steady state to be achieved.
2. Methods 2.1. Study design This was a randomized, open-label, two-way crossover study conducted at a single center. The study began with a screening visit, followed by inpatient hospitalization for 21 days. Subjects received one of the two buprenorphine formulations (8 mg as solution or 16 mg as sublingual tablets) in the first 10-day treatment period and the other formulation in the second 10-day period, with no washout between treatments. Only the data from the tablet maintenance phase are reported here. Physiological and subjective effects were evaluated daily. On day 10 plasma samples were also obtained at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing. Plasma concentrations of buprenorphine were determined according to the method of Moody et al. (1997).
substances (except nicotine or caffeine) were eligible. Subjects were required to be in otherwise good general physical and mental health. Female subjects were required to have a negative pre-study pregnancy test and to use adequate birth control. Potential subjects were ineligible if they tested positive for benzodiazepines at screening, had a known hypersensitivity to buprenorphine or other opioids or received any maintenance medication for ongoing illness. A total of 34 subjects were enrolled. Ten subjects terminated prematurely and 24 (75% male) completed the study. Seven subjects terminated due to noncompliance with protocol; three subjects requested termination. The protocol and consent form were reviewed and approved by the Research and Development Committee (RDC) of the West Los Angeles Veterans Affairs Medical Center and the Institutional Review BoardMedical Human Subject Protection Committee (HSPC) of the University of California at Los Angeles. Informed consent was obtained from all subjects before any study procedures were performed. Subjects were admitted as inpatients approximately 24 h before the first dose and were not discharged until 24 h after the last dose. They were housed in a locked ward and were attended by a study staff member when not in the ward. Subjects were requested not to use any psychoactive drugs or other drugs (except acetaminophen, nicotine, or caffeine) for at least 24 h prior to the first dose of study medication and during the entire study period. No subjects were withdrawn from the study due to adverse events. The most frequently occurring adverse event was headache. 2.3. Medication Two buprenorphine tablets, 8 mg each, were administered sublingually. The sublingual area was inspected 5 min after the administration of buprenorphine tablets and subjects instructed to swallow if the tablets had dissolved. Tablet size was recorded at the 5 and 10 min inspections, and the time of any premature swallows was recorded. Subjects were to swallow at 15 min, whether or not any tablet remained. Subjects were not permitted to eat, drink, or smoke for 1 h before or after administration of study medications. Saliva pH was measured just prior to dosing. No significant difference in mean saliva pH (range 5.03 / 9.90) was found for tablets that dissolved within 5 min or beyond 5 min.
2.2. Subjects 2.4. Opioid effects and withdrawal measures Male or female subjects, 21/55 years old (mean /37), were recruited from the local community by referral and advertisement. Those who met DSM-IV criteria for opioid dependence but were not dependent on other
Respiration rate was evaluated daily prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing on day 10. Pupil diameter was
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
measured daily prior to dosing and at 1, 3, 6, 12 and 24 h following the day 10 dose. Pupil photographs were taken under controlled lighting conditions. For each subject the same eye was photographed on each occasion. Self-reported opioid effects and withdrawal were measured daily prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing on day 10. Subjects rated the degree to which they experienced each of 16 typical opioid effects on a scale of 0 (not at all) to 4 (extremely). Items evaluated were nodding, heavy or sluggish feeling, dry mouth, good mood, energetic, upset stomach, itchy skin, relaxed, coasting, talkative, pleasant sickness, drive, carefree, drunken, friendly, and nervous. The maximum possible score was 64. Subjects rated the degree to which they experienced each of 21 typical opioid withdrawal symptoms on a scale of 0 (not at all) to 4 (extremely). Items evaluated were muscle cramps, flushing, painful joints, yawning, restless, watery eyes, runny nose, chills or gooseflesh, ‘sick to stomach’, sneezing, abdominal cramps, irritable, backache, tense and jittery, sweating, depressed, sleepy, shaky or tremulousness, hot or cold flushes, bothered by noise, and skin clammy and damp. The maximum subject-rated total opioid withdrawal score possible was 84. At the same time that the subject completed these scales, a member of the research staff rated the subject’s symptoms using the same opioid agonist effects and opioid withdrawal scales. 2.5. Statistical analyses Changes in effects over the 24 h interval were assessed using repeated measures ANOVA for the physiological parameters and the non-parametric Friedman related samples test for self-reported and observer-rated scores. Where statistical significance (P B/0.05) was achieved, values for individual time points were compared against baseline values using paired t-tests (for physiological measurements) or the Wilcoxon test (self-reported and observer-rated scores). Data are expressed as mean9/ S.E.M.
3. Results 3.1. Buprenorphine induction Subjects experienced pronounced withdrawal prior to the first dose of buprenorphine, at least 24 h after their last opioid administration. This withdrawal was alleviated over the 10-day induction period. Mean selfreported withdrawal scores were below 10 from day 3.
319
3.2. Opioid effects and opioid withdrawal Pupil diameter changed significantly over the 24 h period (F5, 23 /4.70, P B/0.01) and was significantly lower than baseline at 1 and 3 h after dosing (Fig. 1). No significant changes in respiration rate were observed during the dosing interval (Fig. 1). There was a significant change over the 24 h interval in self-reported opioid effect (x2 /33.7, P B/0.01). Subjects reported a significant decrease in opioid effect (i.e. scores were lower than the baseline values) at 0.5, 1.5, 8, 10 and 12 h after administration, with the maximal decrease occurring at 12 h after dosing. (Fig. 1). Self-reported withdrawal scores did not change significantly over the 24 h period (Fig. 1). No significant changes in opioid effect or opioid withdrawal were reported by observers at any time point following administration (data not shown). 3.3. Individual variations in withdrawal scores Some subjects reported higher withdrawal scores when compared with the rest of the subject population. While a majority of the subjects reported low withdrawal scores before dosing and no changes in withdrawal after dosing, five out of 24 reported a score of at least 10 prior to dosing. Self-reported and observer withdrawal scores for these subjects are presented in Fig. 2. Subjects with more severe withdrawal were not characterized by lower absolute plasma concentrations (Fig. 2, lower panel).
4. Discussion 4.1. Physiological opioid agonist effects The physiological effects produced by buprenorphine in this study were of relatively small magnitude. Pupil diameter, one of the most specific measures of direct opioid effect, decreased significantly following the administration of the drug. The peak effect of buprenorphine on pupil diameter was observed 1 h following administration. However, the pupil effect was of small magnitude with a maximum change of 0.5 mm. In comparison, the reported effect of oral methadone at steady state in methadone patients is a 1.5 mm decrease in pupil diameter (McCaul et al., 1982; Dyer et al., 1999). Furthermore, the pupil diameter returned to baseline values 6 h after the administration of buprenorphine. The effect of methadone is usually of longer duration, up to 12 h after dosing (Dyer et al., 1999). Importantly, the effects of buprenorphine on respiration were insignificant. Buprenorphine has been reported to reduce respiratory rate by 4 breaths per minute in non-opioid dependent individuals at a single
320
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
Fig. 1. Changes in physiological and subjective effects of buprenorphine (16 mg tablet) during dosing interval at day 10. *, Significantly different from the baseline, P B/0.05; **, /P B/0.01.
dose of 4 mg of solution. Higher doses (i.e. 8, 16 and 32 mg) produced effects on respiratory rate similar to that of 4 mg (Walsh et al., 1994). Interestingly, in the same study the administration of methadone in single doses of 15, 30 and 60 mg did not affect respiratory rate in nonopioid dependent subjects. In comparison, in patients maintained on methadone there was a significant reduction in respiratory rate (by /3 breaths per minute) 3 h following methadone administration when compared to the predose values (Dyer et al., 1999). As a partial agonist, buprenorphine could be expected to produce lesser effect on respiratory rate than methadone, but the possibility of cumulative effect with repeated doses could not be ruled out. The present study has demonstrated that there is no evidence of respiratory depression in patients maintained on 16 mg buprenorphine. Since the major feature of opioid overdose is respiratory depression, the dose of buprenorphine used in this study appears very safe. Higher doses have been proposed for alternate-day dosing schedules.
As buprenorphine induced respiratory depression is difficult to reverse with naloxone (Heel et al., 1979; Gal, 1989), future studies should consider the effects of higher doses of buprenorphine on respiration in patients maintained on such doses.
4.2. Self-reported and observer-rated subjective opioid effects and withdrawal Buprenorphine produced ‘negative’ subjective opioid effects (i.e. subjects reported a decrease in opioid effect scores), but there was no associated increase in intensity of withdrawal. Schuh et al. (1999) reported that the positive effect (i.e. ‘high’) of the buprenorphine solution (8 mg a day) in non-opioid dependent heroin users decreased to control values by the fifth day of administration. Together with the data reported here, this suggests that tolerance develops rapidly to the subjective effects of buprenorphine. In addition, Petry et al. (1999, 2000) reported very low opioid agonist effects in subjects
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
321
may also block the effect of any full opioid agonist administered (Schuh et al., 1999). 4.3. Individual variations in withdrawal scores We found individual differences in withdrawal severity, with five subjects reporting higher withdrawal scores when compared with the rest of the subject population (i.e. remaining 19 subjects). The time course showed that the lowest self-reported and observer-rated scores (i.e. a decrease in withdrawal severity) occurred in the period from 3 to 12 h after the administration of the buprenorphine tablet, somewhat later than the time of peak plasma concentration. While absolute plasma concentrations did not differ between these sub-populations of patients, there was a trend for more severe withdrawal to be associated with a faster rate of decline in plasma concentration. A similar association has been found previously in methadone maintained subjects (Dyer et al., 1999).
5. Conclusion
Fig. 2. Individual variations in self-reported and observer-rated withdrawal scores and plasma buprenorphine concentrations in subjects maintained on 16 mg buprenorphine tablet: subjects reporting withdrawal scores of ten or higher at the baseline on day 10 (high withdrawal, n/5) compared with subjects reporting withdrawal scores of less than 10 at the baseline on day 10 (low withdrawal, n/19).
maintained on 4 or 8 mg/70 kg of liquid buprenorphine for 23 days, as well as in subjects receiving double, triple or quadruple dose of the drug in both double blind and open-label studies. Buprenorphine is different in this respect from methadone, which, based on morphinebenzedrine group (MBG scale of the Addiction Research Inventory) scores, produces a significant positive opioid effect lasting from 2 to 5 h after dosing in methadone maintained patients (Dyer et al., 1999). This effect of methadone may interfere with the patient’s everyday activities, as well as contribute to dependence on methadone. The large variations in opioid effect may also contribute to the significant mood disturbances observed in some of these patients (Dyer et al., 2001). In contrast, buprenorphine produces no positive effect in patients maintained on the drug (as shown here) and
In subjects maintained on buprenorphine (16 mg) for 10 days, there was no significant respiratory depression during the dosing interval and the decrease in pupil diameter was of small magnitude. While there was a decrease in opioid effect scores, there was no associated increase in intensity of withdrawal. Consistent with the partial agonist properties of buprenorphine, the magnitude of the effects was not as large as has been previously observed with methadone. Approximately one fifth of subjects experienced clinically significant withdrawal, suggesting that they may require doses higher than 16 mg per day. Future research should attempt a direct comparison of buprenorphine with methadone to confirm whether buprenorphine has an advantage over methadone in producing less direct opioid effects and withdrawal during the dosing interval.
Acknowledgements This project was supported by National Institute on Drug Abuse grants DA 12755 and DA 09260.
References Bickel, W.K., Amass, L., Crean, J.P., Badger, G.J., 1999. Buprenorphine dosing every 1, 2 or 3 days in opioid-dependent patients. Psychopharmacology 146, 111 /118. Bullingham, R.E., McQuay, H.J., Moore, A., Bennett, M.R., 1980. Buprenorphine kinetics. Clin. Pharmacol. Ther. 28, 667 /672. Dyer, K.R., White, J.M., 1997. Patterns of symptom complaints in methadone maintenance patients. Addiction 92, 1445 /1455.
322
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
Dyer, K.R., Foster, D.J.R., White, J.M., Somogyi, A.A., Menelaou, A., Bochner, F., 1999. Steady state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration */effect relationships. Clin. Pharmacol. Ther. 65, 685 / 694. Dyer, K.R., White, J.M., Foster, D.J.R., Bochner, F., Menelaou, A., Somogyi, A.A., 2001. The relationship between mood state and plasma methadone concentration in maintenance patients. J. Clin. Psychopharmacol. 21, 78 /84. Gal, T.J., 1989. Naloxone reversal of buprenorphine-induced respiratory depression. Clin. Pharmacol. Ther. 45, 66 /71. Heel, R.C., Brogden, R.N., Speight, T.M., Avery, G.S., 1979. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs 17, 81 /110. Jasinski, D.R., Pevnick, J.S., Griffith, J.D., 1978. Human pharmacology and abuse potential of the analgesic buprenorphine. Arch. Gen. Psychiatry 35, 501 /516. Johnson, R.E., Chutuape, M.A., Strain, E.C., Walsh, S.L., Stitzer, M.L., Bigelow, G.E., 2000. A comparison of levomethadylacetate, buprenorphine and methadone for opioid dependence. New Engl. J. Med. 343, 1290 /1297. McCaul, M., Bigelow, G., Stitzer, M., Liebson, I., 1982. Short-term effects of oral methadone in methadone maintenance subjects. Clin. Pharm. Ther. 31, 753 /761.
McQuay, H.J., Bullingham, R.E., Paterson, G.M., Moore, R.A., 1980. Clinical effects of buprenorphine during and after operation. Br. J. Anaesth. 52, 1013 /1019. Moody, D.E., Laycock, J.D., Spanbauer, A.C., Crouch, D.J., Foltz, R.L., Josephs, J.L., Amass, I., Bickel, W.K., 1997. Determination of buprenorphine in human plasma by gas chromatograph positive ion chemical ionisation mass spectrometry and liquid chromatography-tandem mass spectrometry. J. Anal. Toxicol. 21, 406 /414. Ohtani, M., Kotaki, H., Sawada, Y., Iga, T., 1995. Comparative analysis of buprenorphine and norbuprenorphine-induced analgesic effects based on pharmacokinetics /pharmacodynamic modeling. J. Pharmacol. Exp. Ther. 272, 505 /510. Petry, N.M., Bickel, W.K., Badger, G.J., 1999. A comparison of four buprenorphine dosing regimens in the treatment of opioid dependence. Clin. Pharmacol. Ther. 66, 306 /314. Petry, N.M., Bickel, W.K., Badger, G.J., 2000. A comparison of four buprenorphine dosing regimens using open-dosing procedures: is twice-weekly dosing possible. Addiction 95, 1069 /1077. Schuh, K.J., Walsh, S.L., Stitzer, M.L., 1999. Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans. Psychopharmacology 145, 162 /174. Walsh, S.L., Preston, K.L., Stitzer, M.L., Cone, E.J., Bigelow, G.E., 1994. Clinical pharmacology of buprenorphine: ceiling effect at high doses. Clin. Pharmacol. Ther. 55, 569 /580.
Opioid effects and opioid withdrawal during a 24 h dosing interval in patients maintained on buprenorphine Olga V. Lopatko a,*, Jason M. White a, Alice Huber b, Walter Ling b a
Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide 5005, SA, Australia b UCLA Integrated Substance Abuse Programs, Los Angeles, CA 90025, USA Received 1 October 2001; accepted 10 October 2002
Abstract In maintenance patients methadone has been shown to produce considerable changes in opioid effects and withdrawal over the dosing interval. As a partial agonist buprenorphine may be expected to produce smaller changes, but the nature and magnitude of these changes have only been described for single doses. In the present study opioid effects and withdrawal were described in patients maintained on buprenorphine. Twenty four opioid dependent subjects were administered 16 mg buprenorphine tablets sublingually for 10 days. On day 10 plasma samples were collected and physiological, subjective and observer-rated measures collected pre-dose and at 14 time points during the dosing interval. No significant respiratory depression was observed. Consistent with the partial agonist properties of buprenorphine, other physiological and subjective changes were also of small magnitude. However, even at a once daily dose of 16 mg some patients experienced significant opioid withdrawal that was maximal at the end of the dosing interval. Buprenorphine maintenance should be associated with a high level of safety and a low level of disruption caused by changing opioid effects over the dosing interval, but some patients may require high doses or other strategies to completely suppress withdrawal. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Buprenorphine; Pharmacodynamics; Addiction; Maintenance
1. Introduction Methadone maintenance is effective in suppressing opioid withdrawal and achieving a range of positive health outcomes in heroin users. A major goal of methadone maintenance is to reduce the fluctuation in opioid effect and opioid withdrawal associated with administration of a short-acting opioid such as heroin. Nevertheless, examination of methadone pharmacodynamics at steady state shows significant opioid effects (e.g. pupil constriction, reduced respiration rate) that are related to changes in methadone concentration over the dosing interval (Dyer et al., 1999). In addition, significant opioid withdrawal is experienced by a subpopulation of patients (Dyer and White, 1997). This is
* Corresponding author. Tel.: /61-88-303-5989 E-mail addresses: [email protected] (O.V. Lopatko), [email protected] (J.M. White), [email protected] (W. Ling).
associated with mood disturbances (Dyer et al., 2001) and is maximal at the time of trough methadone concentration (Dyer et al., 1999). The occurrence of such withdrawal seems unrelated to absolute plasma methadone concentration (Dyer et al., 1999). Buprenorphine is a partial mu-opioid receptor agonist that has been shown to be as effective as methadone in opioid dependence treatment (Johnson et al., 2000). As a partial agonist it produces lower peak effects and milder physical dependence than full agonists such as methadone (Jasinski et al., 1978). As a result, it has greater safety and less abuse potential than methadone, but is effective in blocking both the euphoria and withdrawal produced by other opioids. The pharmacokinetic properties of buprenorphine and the relative safety of high doses allow it to be administered once daily, or, in a significant number of patients, every two, three or even 4 days (Bickel et al., 1999). Individual differences in buprenorphine effectiveness at steady state have not been reported so it is not known whether there
03765-8716/02/$ - see front matter # 2002 Published by Elsevier Science Ireland Ltd. PII: S 0 3 7 6 - 8 7 1 6 ( 0 2 ) 0 0 3 2 2 - 8
318
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
is a subset of patients who experience significant withdrawal towards the end of the dosing interval. To date the relationship between pharmacodynamic and pharmacokinetic parameters of buprenorphine have been reported only for single doses of the drug in both animal (Ohtani et al., 1995) and human (McQuay et al., 1980; Bullingham et al., 1980; Walsh et al., 1994) studies. In healthy male volunteers given a range of doses of buprenorphine sublingually (as solution), Walsh et al. (1994) observed a plateau for the effects of buprenorphine on subjective measures and respiratory depression. If this is true in the chronic dosing situation then it would be expected that opioid effects would show relatively little fluctuation over the buprenorphine dosing interval. To date, there are no published data relevant to this issue. The purpose of the present study was to describe the changes in opioid effects and opioid withdrawal that occur over a 24 h dosing in opioid dependent patients maintained on buprenorphine. In comparison with full agonists such as methadone, the partial agonist buprenorphine would be expected to produce relatively smaller peak opioid effects at doses that are effective in reducing withdrawal. Individual differences in withdrawal severity were also examined. The subjects in this study were administered buprenorphine (16 mg in tablet form) for a period of 10 days to allow steady state to be achieved.
2. Methods 2.1. Study design This was a randomized, open-label, two-way crossover study conducted at a single center. The study began with a screening visit, followed by inpatient hospitalization for 21 days. Subjects received one of the two buprenorphine formulations (8 mg as solution or 16 mg as sublingual tablets) in the first 10-day treatment period and the other formulation in the second 10-day period, with no washout between treatments. Only the data from the tablet maintenance phase are reported here. Physiological and subjective effects were evaluated daily. On day 10 plasma samples were also obtained at pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing. Plasma concentrations of buprenorphine were determined according to the method of Moody et al. (1997).
substances (except nicotine or caffeine) were eligible. Subjects were required to be in otherwise good general physical and mental health. Female subjects were required to have a negative pre-study pregnancy test and to use adequate birth control. Potential subjects were ineligible if they tested positive for benzodiazepines at screening, had a known hypersensitivity to buprenorphine or other opioids or received any maintenance medication for ongoing illness. A total of 34 subjects were enrolled. Ten subjects terminated prematurely and 24 (75% male) completed the study. Seven subjects terminated due to noncompliance with protocol; three subjects requested termination. The protocol and consent form were reviewed and approved by the Research and Development Committee (RDC) of the West Los Angeles Veterans Affairs Medical Center and the Institutional Review BoardMedical Human Subject Protection Committee (HSPC) of the University of California at Los Angeles. Informed consent was obtained from all subjects before any study procedures were performed. Subjects were admitted as inpatients approximately 24 h before the first dose and were not discharged until 24 h after the last dose. They were housed in a locked ward and were attended by a study staff member when not in the ward. Subjects were requested not to use any psychoactive drugs or other drugs (except acetaminophen, nicotine, or caffeine) for at least 24 h prior to the first dose of study medication and during the entire study period. No subjects were withdrawn from the study due to adverse events. The most frequently occurring adverse event was headache. 2.3. Medication Two buprenorphine tablets, 8 mg each, were administered sublingually. The sublingual area was inspected 5 min after the administration of buprenorphine tablets and subjects instructed to swallow if the tablets had dissolved. Tablet size was recorded at the 5 and 10 min inspections, and the time of any premature swallows was recorded. Subjects were to swallow at 15 min, whether or not any tablet remained. Subjects were not permitted to eat, drink, or smoke for 1 h before or after administration of study medications. Saliva pH was measured just prior to dosing. No significant difference in mean saliva pH (range 5.03 / 9.90) was found for tablets that dissolved within 5 min or beyond 5 min.
2.2. Subjects 2.4. Opioid effects and withdrawal measures Male or female subjects, 21/55 years old (mean /37), were recruited from the local community by referral and advertisement. Those who met DSM-IV criteria for opioid dependence but were not dependent on other
Respiration rate was evaluated daily prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing on day 10. Pupil diameter was
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
measured daily prior to dosing and at 1, 3, 6, 12 and 24 h following the day 10 dose. Pupil photographs were taken under controlled lighting conditions. For each subject the same eye was photographed on each occasion. Self-reported opioid effects and withdrawal were measured daily prior to dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16 and 24 h after dosing on day 10. Subjects rated the degree to which they experienced each of 16 typical opioid effects on a scale of 0 (not at all) to 4 (extremely). Items evaluated were nodding, heavy or sluggish feeling, dry mouth, good mood, energetic, upset stomach, itchy skin, relaxed, coasting, talkative, pleasant sickness, drive, carefree, drunken, friendly, and nervous. The maximum possible score was 64. Subjects rated the degree to which they experienced each of 21 typical opioid withdrawal symptoms on a scale of 0 (not at all) to 4 (extremely). Items evaluated were muscle cramps, flushing, painful joints, yawning, restless, watery eyes, runny nose, chills or gooseflesh, ‘sick to stomach’, sneezing, abdominal cramps, irritable, backache, tense and jittery, sweating, depressed, sleepy, shaky or tremulousness, hot or cold flushes, bothered by noise, and skin clammy and damp. The maximum subject-rated total opioid withdrawal score possible was 84. At the same time that the subject completed these scales, a member of the research staff rated the subject’s symptoms using the same opioid agonist effects and opioid withdrawal scales. 2.5. Statistical analyses Changes in effects over the 24 h interval were assessed using repeated measures ANOVA for the physiological parameters and the non-parametric Friedman related samples test for self-reported and observer-rated scores. Where statistical significance (P B/0.05) was achieved, values for individual time points were compared against baseline values using paired t-tests (for physiological measurements) or the Wilcoxon test (self-reported and observer-rated scores). Data are expressed as mean9/ S.E.M.
3. Results 3.1. Buprenorphine induction Subjects experienced pronounced withdrawal prior to the first dose of buprenorphine, at least 24 h after their last opioid administration. This withdrawal was alleviated over the 10-day induction period. Mean selfreported withdrawal scores were below 10 from day 3.
319
3.2. Opioid effects and opioid withdrawal Pupil diameter changed significantly over the 24 h period (F5, 23 /4.70, P B/0.01) and was significantly lower than baseline at 1 and 3 h after dosing (Fig. 1). No significant changes in respiration rate were observed during the dosing interval (Fig. 1). There was a significant change over the 24 h interval in self-reported opioid effect (x2 /33.7, P B/0.01). Subjects reported a significant decrease in opioid effect (i.e. scores were lower than the baseline values) at 0.5, 1.5, 8, 10 and 12 h after administration, with the maximal decrease occurring at 12 h after dosing. (Fig. 1). Self-reported withdrawal scores did not change significantly over the 24 h period (Fig. 1). No significant changes in opioid effect or opioid withdrawal were reported by observers at any time point following administration (data not shown). 3.3. Individual variations in withdrawal scores Some subjects reported higher withdrawal scores when compared with the rest of the subject population. While a majority of the subjects reported low withdrawal scores before dosing and no changes in withdrawal after dosing, five out of 24 reported a score of at least 10 prior to dosing. Self-reported and observer withdrawal scores for these subjects are presented in Fig. 2. Subjects with more severe withdrawal were not characterized by lower absolute plasma concentrations (Fig. 2, lower panel).
4. Discussion 4.1. Physiological opioid agonist effects The physiological effects produced by buprenorphine in this study were of relatively small magnitude. Pupil diameter, one of the most specific measures of direct opioid effect, decreased significantly following the administration of the drug. The peak effect of buprenorphine on pupil diameter was observed 1 h following administration. However, the pupil effect was of small magnitude with a maximum change of 0.5 mm. In comparison, the reported effect of oral methadone at steady state in methadone patients is a 1.5 mm decrease in pupil diameter (McCaul et al., 1982; Dyer et al., 1999). Furthermore, the pupil diameter returned to baseline values 6 h after the administration of buprenorphine. The effect of methadone is usually of longer duration, up to 12 h after dosing (Dyer et al., 1999). Importantly, the effects of buprenorphine on respiration were insignificant. Buprenorphine has been reported to reduce respiratory rate by 4 breaths per minute in non-opioid dependent individuals at a single
320
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
Fig. 1. Changes in physiological and subjective effects of buprenorphine (16 mg tablet) during dosing interval at day 10. *, Significantly different from the baseline, P B/0.05; **, /P B/0.01.
dose of 4 mg of solution. Higher doses (i.e. 8, 16 and 32 mg) produced effects on respiratory rate similar to that of 4 mg (Walsh et al., 1994). Interestingly, in the same study the administration of methadone in single doses of 15, 30 and 60 mg did not affect respiratory rate in nonopioid dependent subjects. In comparison, in patients maintained on methadone there was a significant reduction in respiratory rate (by /3 breaths per minute) 3 h following methadone administration when compared to the predose values (Dyer et al., 1999). As a partial agonist, buprenorphine could be expected to produce lesser effect on respiratory rate than methadone, but the possibility of cumulative effect with repeated doses could not be ruled out. The present study has demonstrated that there is no evidence of respiratory depression in patients maintained on 16 mg buprenorphine. Since the major feature of opioid overdose is respiratory depression, the dose of buprenorphine used in this study appears very safe. Higher doses have been proposed for alternate-day dosing schedules.
As buprenorphine induced respiratory depression is difficult to reverse with naloxone (Heel et al., 1979; Gal, 1989), future studies should consider the effects of higher doses of buprenorphine on respiration in patients maintained on such doses.
4.2. Self-reported and observer-rated subjective opioid effects and withdrawal Buprenorphine produced ‘negative’ subjective opioid effects (i.e. subjects reported a decrease in opioid effect scores), but there was no associated increase in intensity of withdrawal. Schuh et al. (1999) reported that the positive effect (i.e. ‘high’) of the buprenorphine solution (8 mg a day) in non-opioid dependent heroin users decreased to control values by the fifth day of administration. Together with the data reported here, this suggests that tolerance develops rapidly to the subjective effects of buprenorphine. In addition, Petry et al. (1999, 2000) reported very low opioid agonist effects in subjects
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
321
may also block the effect of any full opioid agonist administered (Schuh et al., 1999). 4.3. Individual variations in withdrawal scores We found individual differences in withdrawal severity, with five subjects reporting higher withdrawal scores when compared with the rest of the subject population (i.e. remaining 19 subjects). The time course showed that the lowest self-reported and observer-rated scores (i.e. a decrease in withdrawal severity) occurred in the period from 3 to 12 h after the administration of the buprenorphine tablet, somewhat later than the time of peak plasma concentration. While absolute plasma concentrations did not differ between these sub-populations of patients, there was a trend for more severe withdrawal to be associated with a faster rate of decline in plasma concentration. A similar association has been found previously in methadone maintained subjects (Dyer et al., 1999).
5. Conclusion
Fig. 2. Individual variations in self-reported and observer-rated withdrawal scores and plasma buprenorphine concentrations in subjects maintained on 16 mg buprenorphine tablet: subjects reporting withdrawal scores of ten or higher at the baseline on day 10 (high withdrawal, n/5) compared with subjects reporting withdrawal scores of less than 10 at the baseline on day 10 (low withdrawal, n/19).
maintained on 4 or 8 mg/70 kg of liquid buprenorphine for 23 days, as well as in subjects receiving double, triple or quadruple dose of the drug in both double blind and open-label studies. Buprenorphine is different in this respect from methadone, which, based on morphinebenzedrine group (MBG scale of the Addiction Research Inventory) scores, produces a significant positive opioid effect lasting from 2 to 5 h after dosing in methadone maintained patients (Dyer et al., 1999). This effect of methadone may interfere with the patient’s everyday activities, as well as contribute to dependence on methadone. The large variations in opioid effect may also contribute to the significant mood disturbances observed in some of these patients (Dyer et al., 2001). In contrast, buprenorphine produces no positive effect in patients maintained on the drug (as shown here) and
In subjects maintained on buprenorphine (16 mg) for 10 days, there was no significant respiratory depression during the dosing interval and the decrease in pupil diameter was of small magnitude. While there was a decrease in opioid effect scores, there was no associated increase in intensity of withdrawal. Consistent with the partial agonist properties of buprenorphine, the magnitude of the effects was not as large as has been previously observed with methadone. Approximately one fifth of subjects experienced clinically significant withdrawal, suggesting that they may require doses higher than 16 mg per day. Future research should attempt a direct comparison of buprenorphine with methadone to confirm whether buprenorphine has an advantage over methadone in producing less direct opioid effects and withdrawal during the dosing interval.
Acknowledgements This project was supported by National Institute on Drug Abuse grants DA 12755 and DA 09260.
References Bickel, W.K., Amass, L., Crean, J.P., Badger, G.J., 1999. Buprenorphine dosing every 1, 2 or 3 days in opioid-dependent patients. Psychopharmacology 146, 111 /118. Bullingham, R.E., McQuay, H.J., Moore, A., Bennett, M.R., 1980. Buprenorphine kinetics. Clin. Pharmacol. Ther. 28, 667 /672. Dyer, K.R., White, J.M., 1997. Patterns of symptom complaints in methadone maintenance patients. Addiction 92, 1445 /1455.
322
O.V. Lopatko et al. / Drug and Alcohol Dependence 69 (2003) 317 /322
Dyer, K.R., Foster, D.J.R., White, J.M., Somogyi, A.A., Menelaou, A., Bochner, F., 1999. Steady state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration */effect relationships. Clin. Pharmacol. Ther. 65, 685 / 694. Dyer, K.R., White, J.M., Foster, D.J.R., Bochner, F., Menelaou, A., Somogyi, A.A., 2001. The relationship between mood state and plasma methadone concentration in maintenance patients. J. Clin. Psychopharmacol. 21, 78 /84. Gal, T.J., 1989. Naloxone reversal of buprenorphine-induced respiratory depression. Clin. Pharmacol. Ther. 45, 66 /71. Heel, R.C., Brogden, R.N., Speight, T.M., Avery, G.S., 1979. Buprenorphine: a review of its pharmacological properties and therapeutic efficacy. Drugs 17, 81 /110. Jasinski, D.R., Pevnick, J.S., Griffith, J.D., 1978. Human pharmacology and abuse potential of the analgesic buprenorphine. Arch. Gen. Psychiatry 35, 501 /516. Johnson, R.E., Chutuape, M.A., Strain, E.C., Walsh, S.L., Stitzer, M.L., Bigelow, G.E., 2000. A comparison of levomethadylacetate, buprenorphine and methadone for opioid dependence. New Engl. J. Med. 343, 1290 /1297. McCaul, M., Bigelow, G., Stitzer, M., Liebson, I., 1982. Short-term effects of oral methadone in methadone maintenance subjects. Clin. Pharm. Ther. 31, 753 /761.
McQuay, H.J., Bullingham, R.E., Paterson, G.M., Moore, R.A., 1980. Clinical effects of buprenorphine during and after operation. Br. J. Anaesth. 52, 1013 /1019. Moody, D.E., Laycock, J.D., Spanbauer, A.C., Crouch, D.J., Foltz, R.L., Josephs, J.L., Amass, I., Bickel, W.K., 1997. Determination of buprenorphine in human plasma by gas chromatograph positive ion chemical ionisation mass spectrometry and liquid chromatography-tandem mass spectrometry. J. Anal. Toxicol. 21, 406 /414. Ohtani, M., Kotaki, H., Sawada, Y., Iga, T., 1995. Comparative analysis of buprenorphine and norbuprenorphine-induced analgesic effects based on pharmacokinetics /pharmacodynamic modeling. J. Pharmacol. Exp. Ther. 272, 505 /510. Petry, N.M., Bickel, W.K., Badger, G.J., 1999. A comparison of four buprenorphine dosing regimens in the treatment of opioid dependence. Clin. Pharmacol. Ther. 66, 306 /314. Petry, N.M., Bickel, W.K., Badger, G.J., 2000. A comparison of four buprenorphine dosing regimens using open-dosing procedures: is twice-weekly dosing possible. Addiction 95, 1069 /1077. Schuh, K.J., Walsh, S.L., Stitzer, M.L., 1999. Onset, magnitude and duration of opioid blockade produced by buprenorphine and naltrexone in humans. Psychopharmacology 145, 162 /174. Walsh, S.L., Preston, K.L., Stitzer, M.L., Cone, E.J., Bigelow, G.E., 1994. Clinical pharmacology of buprenorphine: ceiling effect at high doses. Clin. Pharmacol. Ther. 55, 569 /580.