Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-related risk, and to guide management. The auscultatory technique with a trained observer and mercury sphygmomanometer continues to be the method of choice for measurement in the office, using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended. They have the advantage of being able to take multiple measurements. Proper training of observers, positioning of the patient, and selection of cuff size are all essential. It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home. There is increasing evidence that home readings predict cardiovascular events and are particularly useful for monitoring the effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a failure of blood pressure to fall during the night may be associated with increased risk. In obese patients and children, the use of an appropriate cuff size is of paramount importance.

/pdf/recommendations-for-blood-pressure-measurement-in-humans-and-19z5w6eq69.pdf

Recommendations for Blood Pressure Measurement in Humans and Experimental Animals Part 1: Blood Pressure Measurement in Humans: A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research

https://cyberleninka.org/article/n/148766.pdf

Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation

http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

The self-medication hypothesis of addictive disorders derives primarily from clinical observations of patients with substance use disorders. Individuals discover that the specific actions or effects of each class of drugs relieve or change a range of painful affect states. Self-medication factors occur in a context of self-regulation vulnerabilities--primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Persons with substance use disorders suffer in the extreme with their feelings, either being overwhelmed with painful affects or seeming not to feel their emotions at all. Substances of abuse help such individuals to relieve painful affects or to experience or control emotions when they are absent or confusing. Diagnostic studies provide evidence that variously supports and fails to support a self-medication hypothesis of addictive disorders. The cause-consequence controversy involving psychopathology and substance use/abuse is reviewed and critiqued. In contrast, clinical observations and empirical studies that focus on painful affects and subjective states of distress more consistently suggest that such states of suffering are important psychological determinants in using, becoming dependent upon, and relapsing to addictive substances. Subjective states of distress and suffering involved in motives to self-medicate with substances of abuse are considered with respect to nicotine dependence and to schizophrenia and posttraumatic stress disorder comorbid with a substance use disorder.

The Self-medication Hypothesis of Substance Use Disorders: A Reconsideration and Recent Applications

Medications which bind to opioid receptors are increasingly being prescribed for the treatment of multiple and diverse chronic painful conditions. Their use for acute pain or terminal pain is well accepted. Their role in the long-term treatment of chronic noncancer pain is, however, controversial for many reasons. One of the primary reasons is the well-known phenomenon of psychological addiction that can occur with the use of these medications. Abuse and diversion of these medications is a growing problem as the availability of these medications increases and this public health issue confounds their clinical utility. Also, the extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven. Lastly, the role of opioids in the treatment of chronic pain is also influenced by the fact that these potent analgesics are associated with a significant number of side effects and complications. It is these phenomena that are the focus of this review. Common side effects of opioid administration include sedation, dizziness, nausea, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Physical dependence and addiction are clinical concerns that may prevent proper prescribing and in turn inadequate pain management. Less common side effects may include delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. The most common side effects of opioid usage are constipation (which has a very high incidence) and nausea. These 2 side effects can be difficult to manage and frequently tolerance to them does not develop; this is especially true for constipation. They may be severe enough to require opioid discontinuation, and contribute to under-dosing and inadequate analgesia. Several clinical trials are underway to identify adjunct therapies that may mitigate these side effects. Switching opioids and/or routes of administration may also provide benefits for patients. Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events. Opioids can be considered broad spectrum analgesic agents, affecting a wide number of organ systems and influencing a large number of body functions.

/pdf/opioid-complications-and-side-effects-29996mciak.pdf

Opioid complications and side effects.

There has been increasing recognition of the problem of fatal opioid overdose. This review examines the pharmacological basis of respiratory depression following opioid administration. Respiration is controlled principally through medullary respiratory centres with peripheral input from chemoreceptors and other sources. Opioids produce inhibition at the chemoreceptors via mu opioid receptors and in the medulla via mu and delta receptors. While there are a number of neurotransmitters mediating the control of respiration, glutamate and GABA are the major excitatory and inhibitory neurotransmitters, respectively. This explains the potential for interaction of opioids with benzodiazepines and alcohol: both benzodiazepines and alcohol facilitate the inhibitory effect of GABA at the GABAA receptor, while alcohol also decreases the excitatory effect of glutamate at NMDA receptors. Heroin and methadone are the major opioids implicated in fatal overdose. Heroin has three metabolites with opioid activity. Variation in the formation of these metabolites due to genetic factors and the use of other drugs could explain differential sensitivity to overdose. Metabolites of methadone contribute little to its action. However, variation in rate of metabolism due to genetic factors and other drugs used can modify methadone concentration and hence overdose risk. The degree of tolerance also determines risk. Tolerance to respiratory depression is less than complete, and may be slower than tolerance to euphoric and other effects. One consequence of this may be a relatively high risk of overdose among experienced opioid users. While agonist administration modifies receptor function, changes (usually in the opposite direction) also result from use of antagonists. The potential for supersensitivity to opioids following a period of administration of antagonists such as naltrexone warrants further investigation. While our understanding of the pharmacological basis of opioid-related respiratory depression has advanced, better understanding of the role of heroin metabolites, the metabolism of methadone, drug interactions and tolerance would all be of considerable value in knowing how best to respond to this problem.

Mechanisms of fatal opioid overdose.

Aims To characterize the natural history of methamphetamine withdrawal during the first 3 weeks of abstinence. Design Cross-sectional study with comparison group. Setting A substance use treatment facility in Chiang Mai Province, Thailand. Participants The sample comprised 21 in-patients undergoing treatment for methamphetamine dependence. Nine age- and sex-matched non-dependent individuals provided comparison data. Measurements Instruments including: the Amphetamine Withdrawal Ques- tionnaire, a modified version of the Cocaine Selective Severity Assessment, Clin- ical Global Impression scale and the St Mary's Hospital Sleep Questionnaire were completed daily for the first 3 weeks of abstinence. Findings Methamphetamine withdrawal severity declined from a high initial peak within 24 hours of the last use of amphetamines reducing to near control levels by the end of the first week of abstinence (the acute phase). The acute phase of amphetamine withdrawal was characterized by increased sleeping and eating, a cluster of depression-related symptoms and less severely, anxiety and craving-related symptoms. Following the acute withdrawal phase most with- drawal symptoms remained stable and at low levels for the remaining 2 weeks of abstinence. Conclusions This study has provided evidence of a methamphetamine with- drawal syndrome that can be categorized into two phases, the acute phase last- ing 7-10 days during which overall symptom severity declined in a linear pattern from a high initial peak, and a subacute phase lasting at least a further 2 weeks.

The nature, time course and severity of methamphetamine withdrawal.

Opioid substitution treatment for dependence may alter sensitivity to pain. Previous studies on pain sensitivity in methadone maintenance patients have yielded contradictory results. This study compared nociceptive responses between 16 patients on stable, once daily, doses of methadone and 16 matched control subjects. Two types of nociceptive stimuli were used: (1) electrical stimulation; and (2) a cold pressor test. Two parameters were measured: detection for onset of pain, and pain tolerance. Methadone patients were tested over an inter-dosing period: at the time of trough plasma methadone concentration (0 h), and 3 h after their daily dose. Control subjects were tested twice 3 h apart. Blood samples were collected to determine plasma methadone concentration. In methadone patients, trough to peak increases in mean R-(-)- and S-(+)-methadone concentrations (118 and 138 ng/ml to 185 and 259 ng/ml, respectively) resulted in significant increases in pain detection and tolerance values for both nociceptive stimuli. Using electrical stimulation, methadone patients' pain tolerance values were lower than controls at 0 h, but higher than controls at 3 h; no significant differences in pain detection values were found. For the cold pressor test, methadone patients detected pain significantly earlier than controls at 0 h, and were also substantially less pain tolerant than controls at both 0 and 3 h. There were no significant differences in pain detection values between the two groups at 3 h. Pain tolerance to pain detection ratios for methadone patients were significantly lower than controls for the cold pressor test at 0 and 3 h, and for electrical stimulation at 0 h only. In summary, the relative pain sensitivity of methadone maintenance patients is determined by the nature of the nociceptive stimulus (e.g. cold pressor test versus electrical stimulation), the plasma methadone concentration (trough versus peak plasma concentration), and whether thresholds are determined for detection of pain or pain tolerance. Although responding to changes in plasma methadone concentration, maintenance patients are markedly hyperalgesic to pain induced by the cold pressor test.

Hyperalgesic responses in methadone maintenance patients

Aims To assess the efficacy of buprenorphine compared with methadone maintenance therapy for opioid dependence in a large sample using a flexible dosing regime and the marketed buprenorphine tablet. Design Patients were randomized to receive buprenorphine or methadone over a 13-week treatment period in a double-blind, double-dummy trial. Setting Three methadone clinics in Australia. Participants Four hundred and five opioid-dependent patients seeking treatment. Intervention Patients received buprenorphine or methadone as indicated clinically using a flexible dosage regime. During weeks 1‐6, patients were dosed daily. From weeks 7‐13, buprenorphine patients received double their week 6 dose on alternate days. Measurements Retention in treatment, and illicit opioid use as determined by urinalysis. Self-reported drug use, psychological functioning, HIV-risk behaviour, general health and subjective ratings were secondary outcomes. Findings Intention-to-treat analyses revealed no significant difference in completion rates at 13 weeks. Methadone was superior to buprenorphine in time to termination over the 13-week period (Wald c 2 = 4.371, df = 1, P = 0.037), but not separately for the single-day or alternate-day dosing phases. There were no significant between-group differences in morphine-positive urines, or in selfreported heroin or other illicit drug use. The majority (85%) of the buprenorphine patients transferred to alternate-day dosing were maintained in alternate-day dosing. Conclusions Buprenorphine did not differ from methadone in its ability to suppress heroin use, but retained approximately 10% fewer patients. This poorer retention was due possibly to too-slow induction onto buprenorphine. For the majority of patients, buprenorphine can be administered on alternate days.

Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients.

Background Managed withdrawal, or detoxification, is not in itself a treatment for opioid dependence, but it is a required first step for many forms of longer-term treatment. It may also represent the end point of an extensive period of treatment such as methadone maintenance. As such, managed withdrawal is an essential component of an effective treatment system. This review is one of a series that aims to assess the evidence as to the effectiveness of the variety of approaches to managing opioid withdrawal. Objectives To assess the effectiveness of interventions involving the short-term use of buprenorphine to manage the acute phase of opioid withdrawal. Search strategy Multiple electronic databases, including Medline, Embase, Psychlit, Australian Medical Index and Current Contents, were searched using a strategy designed to retrieve references broadly addressing the management of opioid withdrawal. Reference lists of retrieved studies, reviews and conference abstracts were handsearched. Selection criteria We included randomised or quasi-randomised controlled clinical trials or prospective controlled cohort studies comparing buprenorphine (treatment 10 days or less) with another form of treatment. Studies were required to provide detailed information on the type and dose of drugs used and the characteristics of patients treated. Studies were also required to provide information on the nature of withdrawal signs and symptoms experienced, the occurrence of adverse effects OR rates of completion of the withdrawal episode. Data collection and analysis Potentially relevant studies were assessed for inclusion by one reviewer (LG). Inclusion decisions were confirmed by consultation between reviewers. Included studies were assessed by all reviewers. One reviewer (LG) undertook data extraction with the process confirmed by consultation between all three reviewers. Main results Five studies met the criteria for inclusion in the review. No data tables are included in this review and no meta-analysis has been undertaken because of differences in treatment regimes and the assessment of outcomes in these studies. Four studies compared buprenorphine with clonidine. All found withdrawal to be less severe in the buprenorphine treatment group. In three of these studies all participants were withdrawing from heroin. Participants in one study were withdrawing from methadone, with doses reduced to 10mg/day prior to treatment with buprenorphine. Three of the studies commented on residual symptoms experienced by participants treated with buprenorphine to manage heroin withdrawal. Aches, restlessness, yawning, mydriasis, tremor, insomnia, nausea and mild anxiety were reported as being experienced by some participants. Rates of completion of withdrawal were able to be calculated for all studies included in the review but the definition of completion varied between studies. Rates ranged from 65% to 100%. None of the studies included in the review reported adverse effects. However, approximately approximately Lintzeris 1999a approximately approximately (a single-group study which therefore did not meet the inclusion criteria) reported 50% of participants withdrawing from heroin experienced headaches, 28% sedation, 21% nausea, 21% constipation, 21% anxiety, 17% dizziness and 17% itchiness during withdrawal. These adverse effects were most common in the first 2-3 days of treatment and then subsided. In four of the five studies treatment was undertaken on an inpatient basis. Only approximately approximately O'Connor 1997 approximately approximately provided outpatient treatment. However, two studies that did not meet the inclusion criteria ( approximately approximately Diamant 1998 approximately approximately and approximately approximately Lintzeris 1999a approximately approximately ) also provided outpatient treatment. The findings of these studies support the feasibility of heroin withdrawal being managed with buprenorphine on an outpatient basis

Jason M. White

Papers

Mechanisms of fatal opioid overdose.

The nature, time course and severity of methamphetamine withdrawal.

Hyperalgesic responses in methadone maintenance patients

Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients.

Buprenorphine for the management of opioid withdrawal