Buprenorphine Maintenance Subjects Are Hyperalgesic and Have No Antinociceptive Response to a Very High Morphine Dose.

Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline. Subjects were tested at about the time of putative trough plasma buprenorphine concentrations. Setting: Ambulatory. Subjects: Twelve buprenorphine-maintained subjects: once daily sublingual dose (range = 2-22 mg); no dose change for 1.5-12 months. Ten healthy controls. Methods: Intravenous morphine bolus and infusions administered over two hours to achieve two separate pseudo-steady-state plasma concentrations one hour apart. Pain tolerance was assessed by application of nociceptive stimuli (cold pressor [seconds] and electrical stimulation [volts]). Ten blood samples were collected for assay of plasma morphine, buprenorphine, and norbuprenorphine concentrations until three hours after the end of the last infusion; pain tolerance and respiration rate were measured to coincide with blood sampling times. Results: Cold pressor responses (seconds): baseline: control 34 ± 6 vs buprenorphine 17 ± 2 (P = 0.009); morphine infusion-end: control 52 ± 11(P = 0.04), buprenorphine 17 ± 2 (P > 0.5); electrical stimulation responses (volts): baseline: control 65 ± 6 vs buprenorphine 53 ± 5 (P = 0.13); infusion-end: control 74 ± 5 (P = 0.007), buprenorphine 53 ± 5 (P > 0.98). Respiratory rate (breaths per minute): baseline: control 17 vs buprenorphine 14 (P = 0.03); infusion-end: control 15 (P = 0.09), buprenorphine 12 (P < 0.01). Infusion-end plasma morphine concentrations (ng/mL): control 23 ± 1, buprenorphine 136 ± 10. Conclusions: Buprenorphine subjects, compared with controls, were hyperalgesic (cold pressor test), did not experience antinociception, despite high plasma morphine concentrations, and experienced respiratory depression. Clinical implications are discussed.

Heatwaves and their impact on people with alcohol, drug and mental health conditions: a discussion paper on clinical practice considerations.

AIM: This article discusses the clinical implications of adverse health outcomes derived during heatwaves for people with mental health disorders, substance misuse and those taking prescribed medications such as lithium, various neuroleptic and anticholinergic drugs. BACKGROUND: With climate change it is predicted that the incidence of prolonged periods of extreme heat will increase. Specific adverse health outcomes associated with high environmental temperatures include heat stroke and heat exhaustion. Those at increased risk for heat-related mortality are those with chronic health conditions, including those with mental health disorders and substance misuse. DATA SOURCES: Sources of evidence included and 'grey' literature published between 1985 and 2010, such as key texts, empirical research, public policies, training manuals and community information sheets on heat waves. DISCUSSION: Current clinical practice and clinical impact of heatwaves on those people with comorbidity is explored. This includes the physiological components of heat stress, heat regulation, and the impact of alcohol and other drugs; and, ramifications and professional practice issues for those with mental health conditions and those requiring mental health medications. IMPLICATIONS FOR NURSING: Client education covering modification of the environment and the use of client heat safety action plans. Secure, accessible stores of prescribed medication are recommended and emergency substance withdrawal kits could be made available. CONCLUSION: All nurses have a responsibility to increase the capability and resilience of their clients to manage their chronic health needs during a heatwave. At these times nurses need to give extra monitoring and assistance when clients lack the capacity or resources to protect themselves.

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects.

There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose +/- standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 +/- 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.

Methadone maintenance patients are cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations.

Opioid dependent patients require higher than normal doses of opioid analgesics. However, this regimen has not been formally tested. This study utilised a double-blind placebo-controlled design to examine antinociceptive responses to saline and pseudo-steady-state plasma morphine concentrations (173+/-11 (mean+/-SEM), range 106-305 ng/ml) in 18 methadone participants in three stable, once daily methadone dose ranges 11-45 mg (n=6), 46-80 mg (n=6), 81-115 mg (n=6) and 10 controls. Testing commenced approximately 20 h after the maintenance dose with the next dose given 1h after morphine cessation. Nociceptive stimuli (cold pressor (seconds) and electrical stimulation (volts)) were used to measure pain detection threshold and pain tolerance. Blood samples were analysed by HPLC for plasma morphine and R-(-)-methadone concentrations. Methadone participants were hyperalgesic to cold pressor pain. High plasma morphine concentrations failed to significantly change cold pressor and electrical stimulation pain tolerance for methadone patients, but in controls, morphine significantly (P<0.05) increased mean pain tolerance to cold pressor by 59+/-29% (range -17% to 311%) and electrical stimulation by 19+/-6% (range 0% to 58%). Morphine significantly (P<0.05) decreased respiration rates by 12+/-3% (range -29% to 8%) in methadone subjects. On saline days, rising methadone concentrations significantly (P<0.01) increased cold pressor pain detection threshold by 32+/-6% (range 1-81%) and cold pressor pain tolerance by 23+/-6% (range -32% to 56%). Methadone maintained patients are hyperalgesic and cross-tolerant to the antinociceptive effects of very high plasma morphine concentrations. While even higher morphine doses may achieve some pain relief, this may be at the cost of unacceptable respiratory depression.

Vasodepressor syncope and the diagnostic accuracy of the head-up tilt test with sublingual glyceryl trinitrate.

Thirteen syncopal subjects and thirteen asymptomatic controls were examined by head-up tilt (HUT) with and without sublingual GTN. Adding GTN to HUT improved the sensitivity of the test (8 % to 46%) but decreased specificity (100 % to 54 %).

Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity.

This study sought to characterize antagonist-precipitated heroin withdrawal during and immediately following anaesthesia and to identify the determinants of withdrawal severity and duration in 48 dependent heroin users. Objective withdrawal signs decreased significantly with each naloxone bolus administered under anaesthetic. The cost (amount) of the final heroin administration and the number of hours between last heroin use and commencement of anaesthesia were significant, independent predictors of the severity of withdrawal symptomatology. While 83% (40/48) of participants completed withdrawal according to objective criteria and commenced maintenance naltrexone treatment, almost half (22/48) were unable to commence naltrexone on the day of the procedure due to residual withdrawal signs. Fourteen of these 22 participants subsequently commenced naltrexone (median number of days between admission and commencement of naltrexone was 2, range 1 - 6) while eight left treatment prior to initiation of naltrexone. Significantly fewer of those with more severe withdrawal signs during anaesthesia commenced naltrexone (40% vs. 60%). While the severity and duration of withdrawal symptomatology may be moderated by encouraging participants to reduce (or cease) heroin use close to the time of withdrawal, for a substantial proportion of participants in this study, heroin withdrawal by this antagonist-precipitated procedure was neither rapid nor painless. [Ali R, Thomas P, White J, McGregor C, Danz,C, Gowing L, Stegink A, Athanasos P. Antagonist-precipitated heroin withdrawal under anaesthetic prior to maintenance naltrexone treatment: determinants of withdrawal severity.

Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study.

Hyperalgesia has been demonstrated to be a cardinal sign of physical withdrawal from opioids in preclinical models for more than 30 years, although few empirical data exist to support its occurrence in humans. In this preliminary study we used the acute opioid physical dependence (APD) model to test for the presence of hyperalgesia to experimental cold-pressor pain in 4 healthy non-opioid-dependent men via 3 different pretreatment opioid administration protocols previously demonstrated to induce APD (morphine 18 mg/70 kg intramuscular, morphine 10 mg/70 kg intravenous, hydromorphone 2 mg/70 kg intravenous), repeated on 2 separate occasions, and placebo. Cold-pressor pain threshold and tolerance were examined before opioid administration and 5 and 15 minutes after precipitated withdrawal with naloxone 10 mg/70 kg intravenous. Paired t tests comparing change scores between the opioid pretreatments and placebo showed that pain threshold and tolerance to the cold-pressor uniformly decreased across all APD induction methods, and the effect size was large (approximately 70% of baseline) and reproducible. These findings provide initial support for the existence of opioid-induced hyperalgesia, which has been conceptualized as a coexisting opponent process to opioid-induced analgesia and proposed to be an alternative explanation for the development of analgesic tolerance to opioids.

Chronic pain, substance abuse and addiction.

Health care professionals face numerous challenges in assessing and treating chronic pain patients with a substance abuse history. Societal perspectives on morality and criminality, imprecise addiction terminology, litigation fears, and genuine concern for a patient's relapse into or escalation of substance abuse result in unrelieved and under-relieved pain in precisely the population that--as increasing evidence indicates--is generally intolerant of pain. Before adequate pain relief can occur in chronic pain patients with current or past substance abuse issues, it is imperative that the clinician recognize addiction as a disease with known symptoms and treatments. Further, the clinician must realize the difference between true addiction and similar conditions, so the patient's condition can be monitored and regulated properly. Although clinicians are often reluctant to medicate with opioids, it is always best to err on the side of adequate pain relief. Withholding opioids from chronic pain patients in order to avoid the onset or relapse of addiction is contrary to the growing body of evidence and results only in unnecessary pain for the patient. Chronic pain in patients with a history of addictive disease can be treated successfully with opiate analgesia; it just requires caution and careful monitoring of medication use. If addiction is treated as a known risk when providing opioid analgesia to a recovering addict, its development can be minimized while pain relief is provided.