Background Optimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. F... more Background Optimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. Full agonist treatment of BPOW is limited by buprenorphine’s high-affinity blockade at mu-opioid receptors (μORs). Buprenorphine’s partial agonism (low intrinsic efficacy) at μORs can limit the effectiveness of even massive doses once BPOW has begun. Adjunct medications, such as clonidine, are rarely effective in severe BPOW. Ketamine is an N-methyl-D-aspartate receptor antagonist with a potentially ideal pharmacologic profile for treatment of BPOW. Ketamine reduces opioid withdrawal symptoms independently of direct μOR binding, synergistically potentiates the effectiveness of buprenorphine μOR signaling, reverses (resensitizes) fentanyl induced μOR receptor desensitization, and inhibits descending pathways of hyperalgesia and central sensitization. Ketamine’s rapid antidepressant effects potentially address depressive symptoms and subjective distress that often accompanies BPOW. Ketamine is inexpensive, safe, and available in emergency departments. To date, neither ketamine as treatment for BPOW nor to support uncomplicated buprenorphine induction has been described. Case Description We report a case of an illicit fentanyl-using OUD patient who experienced severe BPOW during an outpatient low-dose cross taper buprenorphine induction (ie, “microdose”). The BPOW was successfully treated in the emergency department with a combination of ketamine (0.6 mg/kg intravenous over 1 hour) combined with high-dose buprenorphine (16 mg sublingual single dose); 3 days later he was administered a month-long dose of extended-release subcutaneous buprenorphine which was repeated monthly (300 mg). At 90 days the patient remained in treatment and reported continuous abstinence from fentanyl use. Conclusions This single case observation raises important questions about the potential therapeutic role of ketamine as a treatment for BPOW. BPOW is an important clinical problem for which there is currently only limited guidance and no universally accepted approach. Prospective study comparing the effectiveness of differing pharmacologic approaches to treat BPOW is urgently needed.
PurposeImproved life expectancy has increased the likelihood for long-term complications from che... more PurposeImproved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort.MethodsThe population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN.ResultsCIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02–7.46); and (colorectal: 5.37, 2.69–10.73), lower risk for older age at diagnosis (0.66, 0.53–0.83) and divorced/separated marital status (2.13, 1.42–3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08–1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09–1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06–2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07–2.35).ConclusionsCIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.
Background: Previous clinical studies have not examined the relationship between nicotine abstine... more Background: Previous clinical studies have not examined the relationship between nicotine abstinence and opioid use for postoperative analgesia. This may be important because tobacco smokers are routinely required to abstain from smoking just before and during acute post-surgical recovery. This study investigated IV morphine self-administration [patient controlled analgesia (PCA)], subjective pain/drug effects and other measures during post-operative (elective Cesarean section) recovery. Material/methods: Seven females, selected to vary in nicotine use [4 non-using controls (CON), 3 users (NIC)], completed the protocol. Gender, time and type of surgery, and pre- and intra-operative medications were controlled. Subject assessments included the McGill Pain Questionnaire and the Profile of Mood States; drug effects were measured using the Addiction Research Center Inventory. Results: Mean (M +/-SD) 24-hr morphine responding (button-pressing requests) was significantly higher for NIC (M=183+/-50) than CON (M=38+/-10). Weight-adjusted morphine use (mg/kg/24 hr) was significantly higher for NIC (M=1.80+/-0.23) than CON (M=0.64+/-0.14). Although the groups reported similar pain severity following morphine loading, NIC patients reported significantly greater pain severity than CON patients after 24 hr PCA. Conclusions: These preliminary data suggest that a history of nicotine use and/or short-term nicotine abstinence can modulate morphine use and analgesia during post-operative recovery. These procedures provide a model for studying patterns and determinants of analgesic self-administration in medical settings.
We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can ... more We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can modulate naloxone-precipitated withdrawal effects. Such information could help determine its receptor mechanism of action and whether dynorphin is useful for treating opioid dependence. Six opioid-experienced subjects participated in a within-subject, placebo-controlled design. There were two phases, each with four test sessions. In phase 1, volunteers who were not physically dependent were administered 0, 0.1, 0.32 and 1 mg/kg dynorphin (15-min i.v. infusion) in ascending order, and subjective, observer-rated and physiological effects were monitored. Dynorphin produced brief, dose-related increases in drug effect ratings with both good and bad drug effects reported by different subjects. There were no significant changes in pupil size, respiratory rate, skin temperature, heart rate or blood pressure, These data are consistent with preclinical findings that dynorphin has a short duration of action and does not primarily exert its direct effects through mu-opioid receptors. In four separate sessions of phase 2, acute morphine pretreatment (45 mg/70 kg i.m.) was followed 15 or 18 hr later by dynorphin (0 vs. 1 mg/kg, 15-min i.v.) and then naloxone (1 or 3 vs. 10 mg/70 kg, 5-min i.v.). Under these conditions, dynorphin weakly potentiated naloxone-precipitated withdrawal. These data contrast with those of previous preclinical studies showing dependence-attenuating effects of dynorphin and fail to support its use as an antiwithdrawal agent in humans.
The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteer... more The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.
Two studies were conducted to quantify biological and behavioral effects resulting from exposure ... more Two studies were conducted to quantify biological and behavioral effects resulting from exposure to controlled doses of marijuana smoke. In one study, puff volume (30, 60 and 90 ml) and in a second study, breathhold duration (0, 10 and 20 sec) were systematically varied while holding constant other smoking topography parameters (number of puffs = 10, interpuff interval = 60 sec and inhalation volume = 25% of vital capacity). Each study also varied levels of delta 9-tetrahydro-cannabinol marijuana cigarette content (1.75% and 3.55%). Regular marijuana users served as subjects (n = 7 in each experiment). Subjects smoked 10 puffs in each of six sessions; a seventh, nonsmoking session (all measures recorded at the same times as in active smoking sessions) served as a control. Variations in puff volume produced significant dose-related changes in postsmoking plasma delta 9-tetrahydro-cannabinol levels, carbon monoxide boost and subjective effects (e.g., "high"). In contrast, breathholding for 10 or 20 sec versus 0 sec increased plasma delta 9-tetrahydro-cannabinol levels but not CO boost or subjective effects. Task performance measures were not reliably influenced by marijuana smoke exposure within the dosing ranges examined. These findings confirm the utility of the controlled smoking technology, support the notion that cumulative puff volume systematically influences biological exposure and subjective effects, but cast doubt on the common belief that prolonged breathholding of marijuana smoke enhances classical subjective effects associated with its reinforcing value in humans.
Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioi... more Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioid dependence. One potential advantage of buprenorphine over full mu opioid agonists is its reported low physical dependence profile. This study systematically examined physical dependence produced by maintenance with a clinically relevant dose of buprenorphine using antagonist challenge procedures. In this residential laboratory study, eight opioid-dependent volunteers maintained on 8 mg/day of sublingual buprenorphine were each challenged on independent occasions with placebo, i.m. naloxone (0.3, 1.0, 3.0 and 10.0 mg/70 kg) and p.o. naltrexone (0.3, 1.0 and 3.0 mg/70 kg) 14 hr after their daily buprenorphine dose using a repeated measures, cross-over design. Both naloxone and naltrexone precipitated time- and dose-dependent withdrawal, as evidenced by changes in subject-rated, observer-rated and physiological measures. Significant precipitated withdrawal occurred at 3.0 and 10 mg/70 kg i.m. of naloxone and 3.0 mg/70 kg p.o. of naltrexone. These results indicate that buprenorphine maintenance produces physical dependence and that i.m. naloxone and p.o. naltrexone produce equivalent effects in withdrawal precipitation under these conditions. Findings have implications for selection of antagonist doses for use in formulating combination agonist/antagonist medications and for use in transition of drug abusers from buprenorphine to antagonist maintenance therapies.
Experimental and Clinical Psychopharmacology, 2005
This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase o... more This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase opioid craving and seeking behavior. The author used a 3 x 2 within-subject randomized crossover design to assess craving and operant behavioral effects of 3 pretreatments (naloxone 0.1 mg/70 kg, fentanyl 0.75 mg/70 kg, or saline iv) and drug or money reinforcement opportunity in 8 methadone-maintained volunteers. Each pretreatment was paired with response-contingent (15 x fixed-ratio 100) delivery of drug (fentanyl 1.5 mg/70 kg iv) and money (rated equivalent of fentanyl) in different sessions. Naloxone significantly increased opioid craving, withdrawal signs, and symptoms, but not operant behavior, relative to saline and fentanyl pretreatment. However, drug versus money reinforcement opportunity did not significantly increase opioid craving or seeking behavior.
Background Optimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. F... more Background Optimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. Full agonist treatment of BPOW is limited by buprenorphine’s high-affinity blockade at mu-opioid receptors (μORs). Buprenorphine’s partial agonism (low intrinsic efficacy) at μORs can limit the effectiveness of even massive doses once BPOW has begun. Adjunct medications, such as clonidine, are rarely effective in severe BPOW. Ketamine is an N-methyl-D-aspartate receptor antagonist with a potentially ideal pharmacologic profile for treatment of BPOW. Ketamine reduces opioid withdrawal symptoms independently of direct μOR binding, synergistically potentiates the effectiveness of buprenorphine μOR signaling, reverses (resensitizes) fentanyl induced μOR receptor desensitization, and inhibits descending pathways of hyperalgesia and central sensitization. Ketamine’s rapid antidepressant effects potentially address depressive symptoms and subjective distress that often accompanies BPOW. Ketamine is inexpensive, safe, and available in emergency departments. To date, neither ketamine as treatment for BPOW nor to support uncomplicated buprenorphine induction has been described. Case Description We report a case of an illicit fentanyl-using OUD patient who experienced severe BPOW during an outpatient low-dose cross taper buprenorphine induction (ie, “microdose”). The BPOW was successfully treated in the emergency department with a combination of ketamine (0.6 mg/kg intravenous over 1 hour) combined with high-dose buprenorphine (16 mg sublingual single dose); 3 days later he was administered a month-long dose of extended-release subcutaneous buprenorphine which was repeated monthly (300 mg). At 90 days the patient remained in treatment and reported continuous abstinence from fentanyl use. Conclusions This single case observation raises important questions about the potential therapeutic role of ketamine as a treatment for BPOW. BPOW is an important clinical problem for which there is currently only limited guidance and no universally accepted approach. Prospective study comparing the effectiveness of differing pharmacologic approaches to treat BPOW is urgently needed.
PurposeImproved life expectancy has increased the likelihood for long-term complications from che... more PurposeImproved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort.MethodsThe population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN.ResultsCIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02–7.46); and (colorectal: 5.37, 2.69–10.73), lower risk for older age at diagnosis (0.66, 0.53–0.83) and divorced/separated marital status (2.13, 1.42–3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08–1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09–1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06–2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07–2.35).ConclusionsCIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.
Background: Previous clinical studies have not examined the relationship between nicotine abstine... more Background: Previous clinical studies have not examined the relationship between nicotine abstinence and opioid use for postoperative analgesia. This may be important because tobacco smokers are routinely required to abstain from smoking just before and during acute post-surgical recovery. This study investigated IV morphine self-administration [patient controlled analgesia (PCA)], subjective pain/drug effects and other measures during post-operative (elective Cesarean section) recovery. Material/methods: Seven females, selected to vary in nicotine use [4 non-using controls (CON), 3 users (NIC)], completed the protocol. Gender, time and type of surgery, and pre- and intra-operative medications were controlled. Subject assessments included the McGill Pain Questionnaire and the Profile of Mood States; drug effects were measured using the Addiction Research Center Inventory. Results: Mean (M +/-SD) 24-hr morphine responding (button-pressing requests) was significantly higher for NIC (M=183+/-50) than CON (M=38+/-10). Weight-adjusted morphine use (mg/kg/24 hr) was significantly higher for NIC (M=1.80+/-0.23) than CON (M=0.64+/-0.14). Although the groups reported similar pain severity following morphine loading, NIC patients reported significantly greater pain severity than CON patients after 24 hr PCA. Conclusions: These preliminary data suggest that a history of nicotine use and/or short-term nicotine abstinence can modulate morphine use and analgesia during post-operative recovery. These procedures provide a model for studying patterns and determinants of analgesic self-administration in medical settings.
We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can ... more We evaluated the human pharmacology of dynorphin A(1-13) and determined whether this peptide can modulate naloxone-precipitated withdrawal effects. Such information could help determine its receptor mechanism of action and whether dynorphin is useful for treating opioid dependence. Six opioid-experienced subjects participated in a within-subject, placebo-controlled design. There were two phases, each with four test sessions. In phase 1, volunteers who were not physically dependent were administered 0, 0.1, 0.32 and 1 mg/kg dynorphin (15-min i.v. infusion) in ascending order, and subjective, observer-rated and physiological effects were monitored. Dynorphin produced brief, dose-related increases in drug effect ratings with both good and bad drug effects reported by different subjects. There were no significant changes in pupil size, respiratory rate, skin temperature, heart rate or blood pressure, These data are consistent with preclinical findings that dynorphin has a short duration of action and does not primarily exert its direct effects through mu-opioid receptors. In four separate sessions of phase 2, acute morphine pretreatment (45 mg/70 kg i.m.) was followed 15 or 18 hr later by dynorphin (0 vs. 1 mg/kg, 15-min i.v.) and then naloxone (1 or 3 vs. 10 mg/70 kg, 5-min i.v.). Under these conditions, dynorphin weakly potentiated naloxone-precipitated withdrawal. These data contrast with those of previous preclinical studies showing dependence-attenuating effects of dynorphin and fail to support its use as an antiwithdrawal agent in humans.
The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteer... more The clinical pharmacology of fentanyl and alfentanil was examined in opioid-experienced volunteers with agonist and antagonist sensitivity measures. Two studies used within-subject, placebo-controlled, crossover designs. In study 1, fentanyl (0.125, 0.25 mg/70 kg i.v.) was followed at 0, 20, 60 and 180 min by naloxone (10 mg/70 kg i.m.). Agonist effects during 180-min and 0-min (control; simultaneous fentanyl-naloxone i.v. infusion) challenge sessions were compared. Fentanyl rapidly constricted pupils, depressed respiration and produced subjective "high" and opiate symptoms lasting 60 to 120 min, depending on the measure. Naloxone precipitated withdrawal symptoms of comparable intensity at each challenge point. In study 2, fentanyl (0.125, 0.25 mg/70 kg i.v.), alfentanil (1, 2 mg/70 kg i.v.) and saline were followed at 1 and 6 hr by naloxone (10 mg/70 kg i.m.). Agonist effects were examined during 6-hr challenge sessions. The two drugs produced a comparable range of effects with similar peak magnitude for 0.125 mg/70 kg fentanyl and 1 mg/70 kg alfentanil and for 0.25 mg/70 kg fentanyl and 2 mg/70 kg alfentanil. Alfentanil's duration of action was brief ( < 60 min). Withdrawal was precipitated at 6 hr only after 0.25 mg/70 kg fentanyl. These findings support typical mu opioid characteristics (pleasurable subjective effects, physical dependence) for both drugs, differential duration of action (fentanyl > alfentanil) and peak effects consistent with a 1:8 (fentanyl/alfentanil) potency ratio.
Two studies were conducted to quantify biological and behavioral effects resulting from exposure ... more Two studies were conducted to quantify biological and behavioral effects resulting from exposure to controlled doses of marijuana smoke. In one study, puff volume (30, 60 and 90 ml) and in a second study, breathhold duration (0, 10 and 20 sec) were systematically varied while holding constant other smoking topography parameters (number of puffs = 10, interpuff interval = 60 sec and inhalation volume = 25% of vital capacity). Each study also varied levels of delta 9-tetrahydro-cannabinol marijuana cigarette content (1.75% and 3.55%). Regular marijuana users served as subjects (n = 7 in each experiment). Subjects smoked 10 puffs in each of six sessions; a seventh, nonsmoking session (all measures recorded at the same times as in active smoking sessions) served as a control. Variations in puff volume produced significant dose-related changes in postsmoking plasma delta 9-tetrahydro-cannabinol levels, carbon monoxide boost and subjective effects (e.g., "high"). In contrast, breathholding for 10 or 20 sec versus 0 sec increased plasma delta 9-tetrahydro-cannabinol levels but not CO boost or subjective effects. Task performance measures were not reliably influenced by marijuana smoke exposure within the dosing ranges examined. These findings confirm the utility of the controlled smoking technology, support the notion that cumulative puff volume systematically influences biological exposure and subjective effects, but cast doubt on the common belief that prolonged breathholding of marijuana smoke enhances classical subjective effects associated with its reinforcing value in humans.
Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioi... more Buprenorphine is a partial mu opioid agonist with demonstrated efficacy in the treatment of opioid dependence. One potential advantage of buprenorphine over full mu opioid agonists is its reported low physical dependence profile. This study systematically examined physical dependence produced by maintenance with a clinically relevant dose of buprenorphine using antagonist challenge procedures. In this residential laboratory study, eight opioid-dependent volunteers maintained on 8 mg/day of sublingual buprenorphine were each challenged on independent occasions with placebo, i.m. naloxone (0.3, 1.0, 3.0 and 10.0 mg/70 kg) and p.o. naltrexone (0.3, 1.0 and 3.0 mg/70 kg) 14 hr after their daily buprenorphine dose using a repeated measures, cross-over design. Both naloxone and naltrexone precipitated time- and dose-dependent withdrawal, as evidenced by changes in subject-rated, observer-rated and physiological measures. Significant precipitated withdrawal occurred at 3.0 and 10 mg/70 kg i.m. of naloxone and 3.0 mg/70 kg p.o. of naltrexone. These results indicate that buprenorphine maintenance produces physical dependence and that i.m. naloxone and p.o. naltrexone produce equivalent effects in withdrawal precipitation under these conditions. Findings have implications for selection of antagonist doses for use in formulating combination agonist/antagonist medications and for use in transition of drug abusers from buprenorphine to antagonist maintenance therapies.
Experimental and Clinical Psychopharmacology, 2005
This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase o... more This study examined whether acute opioid withdrawal and drug reinforcement opportunity increase opioid craving and seeking behavior. The author used a 3 x 2 within-subject randomized crossover design to assess craving and operant behavioral effects of 3 pretreatments (naloxone 0.1 mg/70 kg, fentanyl 0.75 mg/70 kg, or saline iv) and drug or money reinforcement opportunity in 8 methadone-maintained volunteers. Each pretreatment was paired with response-contingent (15 x fixed-ratio 100) delivery of drug (fentanyl 1.5 mg/70 kg iv) and money (rated equivalent of fentanyl) in different sessions. Naloxone significantly increased opioid craving, withdrawal signs, and symptoms, but not operant behavior, relative to saline and fentanyl pretreatment. However, drug versus money reinforcement opportunity did not significantly increase opioid craving or seeking behavior.
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