Assessment of tolerance to the effects of methamphetamine on daytime and nighttime activity evaluated with actigraphy in rhesus monkeys.

RATIONALE: Methamphetamine is one of the most largely consumed illicit drugs, and its use is associated with abuse liability and several adverse health effects, such as sleep impairment. Importantly, sleep quality can influence addiction treatment outcomes. Evidence suggests that tolerance can develop to the sleep-disrupting effects of stimulant drugs. OBJECTIVE: The aim of the present study was to investigate the development of tolerance to the actigraphy-based sleep-disrupting and stimulant effects of methamphetamine self-administration in rhesus monkeys. METHODS: Methamphetamine (0.03 mg/kg/inf, i.v.) self-administration was carried out following three different protocols: 14 consecutive days of self-administration, 5 days/week for 3 weeks, with a 2-day interval between 5-day blocks of self-administration, and 3 days/week for 3 weeks, with a 4-day interval between 3-day blocks of self-administration. Daytime activity and activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline parameters) and throughout each protocol. RESULTS: Methamphetamine self-administration markedly disrupted sleep-like measures and increased daytime activity. Tolerance developed to those effects with repeated methamphetamine intake exceeding five consecutive days. Inclusion of washout periods (2 or 4 days) between blocks of methamphetamine self-administration attenuated the development of tolerance, with longer breaks from methamphetamine intake being more effective in maintaining the sleep-disrupting and stimulant effects of methamphetamine. CONCLUSIONS: Tolerance can develop to the stimulant and sleep-disrupting effects of methamphetamine self-administration. Interruption of drug intake extends the effects of methamphetamine on sleep-like measures and daytime activity.

Blood testing in chronic pain management.

Blood testing is quickly becoming a useful laboratory tool for opioid prescribers who wish to document and assess patient tolerance, more objectively monitor patient safety, and evaluate patient compliance using information that is not available with traditional urine drug testing (UDT). Blood testing does not need to be performed as frequently as UDT but provides extremely valuable information which can be used to more accurately evaluate patient compliance and assist with interpreting blood toxicology results commonly used in impairment or overdose cases. This narrative review presents the current evidence supporting the use of blood testing within the chronic pain management setting. In addition, this review aims to introduce and discuss the role of routine blood testing within the chronic pain management setting. Blood testing for the purpose of documenting opioid tolerance is a relatively novel tool for pain physicians and as such this review is not intended to be a comprehensive or exhaustive review of the scientific or medical literature. Prescribers must also be aware that this type of laboratory testing need only be administered to chronic pain patients receiving daily opioid therapy. Patients taking infrequent, low dose, or as needed medications are not anticipated to benefit from this type of test. Based on the complexity of both achieving acceptable outcomes with opioid treatment and the legal and societal issues at hand, we feel that the addition of blood concentration levels will become the standard of care in the near future.

Chronic methadone treatment shows a better cost/benefit ratio than chronic morphine in mice.

Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading µ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

Respiratory failure following delayed intrathecal morphine pump refill: a valuable, but costly lesson.

BACKGROUND: Spinal analgesia, mediated by opioid receptors, requires only a fraction of the opioid dose that is needed systemically. By infusing a small amount of opioid into the cerebrospinal fluid in close proximity to the receptor sites in the spinal cord, profound analgesia may be achieved while sparing some of the side effects due to systemic opioids. Intraspinal drug delivery (IDD) has been increasingly used in patients with intractable chronic pain, when these patients have developed untoward side effects with systemic opioid usage. The introduction of intrathecal opioids has been considered one of the most important breakthroughs in pain management in the past three decades. A variety of side effects associated with the long-term usage of IDD have been recognized. Among them, respiratory depression is the most feared. OBJECTIVE: To describe a severe adverse event, i.e., respiratory failure, following delayed intrathecal morphine pump refill. CASE REPORT: A 65-year-old woman with intractable chronic low back pain, due to degenerative disc disease, and was referred to our clinic for an intraspinal drug delivery evaluation, after failing to respond to multidisciplinary pain treatment. Following a psychological evaluation confirming her candidacy, she underwent an outpatient patient-controlled continuous epidural morphine infusion trial. The infusion trial lasted 12 days and was beneficial in controlling her pain. The patient reported more than 90% pain reduction with improved distance for ambulation. She subsequently consented and was scheduled for permanent intrathecal morphine pump implantation. The intrathecal catheter was inserted at right paramedian L3-L4, with catheter tip advanced to L1, confirmed under fluoroscopy. Intrathecal catheter placement was confirmed by positive CSF flow and by myelogram. A non-programmable Codman 3000 constant-flow rate infusion pump was placed in the right mid quandrant between right rib cage and right iliac crest. The intrathecal infusion consisted of preservative free morphine, delivering 1.0 mg /day. Over the following 6 months, the dosage was gradually titrated up to 4 mg/day with satisfactory pain control without significant side effects. However, the patient was not able to return to the clinic for pump refill until 12 days later than the previously scheduled pump-refill date. Her pump was accessed and was noted to be empty. Her intrathecal pump was refilled with preservative free morphine, delivering 4 mg/day (the same daily dose as her previous refill). However, on the night of pump refill, 10 hours after the pump refill, the patient was found to be unresponsive by her family members. 911 was called. Upon arriving, paramedics found her in respiratory failure, with shallow breathing at a rate of 5/min, pulse oxymetry showing oxygen saturation about 55-58%. She was emergently intubated on site and rushed to local hospital ER. The on call physician for our clinic was immediately contacted, and advised the administration of intravenous Naloxone. Her respiratory effort improved dramatically after receiving a total of 0.6 mg IV Naloxone IV over 25 minutes. Her intrathecal pump was immediately accessed by clinic on call physician and the remainder of the medication in the catheter space was aspirated. The pump infusate was immediately diluted with preservative free normal saline, to deliver preservative free morphine at 1mg/day. She was transferred to the intensive care unit and extubated the next morning. She recovered fully without any sequelae. CONCLUSION: Loss of opioid tolerance due to delayed pump refill may subject patients to the development of severe respiratory depression. Meticulous approach should be employed when refilling pumps in these patients when their pumps are completely empty. To our knowledge, this is the first reported case of this type.

Biological cost of tolerance to heavy metals in the mosquito Anopheles gambiae.

The global rate of heavy metal pollution is rapidly increasing in various habitats. Anopheles malaria vector species (Diptera: Culicidae) appear to tolerate many aquatic habitats with metal pollutants, despite their normal proclivity for 'clean' water (i.e. low levels of organic matter). Investigations were conducted to establish whether there are biological costs for tolerance to heavy metals in Anopheles gambiae Giles sensu stricto and to assess the potential impact of heavy metal pollution on mosquito ecology. Anopheles gambiae s.s. were selected for cadmium, copper or lead tolerance through chronic exposure of immature stages to solutions of the metals for three successive generations. Biological costs were assessed in the fourth generation by horizontal life table analysis. Tolerance in larvae to cadmium (as cadmium chloride, CdCl(2)), copper [as copper II nitrate hydrate, Cu(NO(3))(2) 2.5 H(2)O] and lead [as lead II nitrate, Pb(NO(3))(2)], monitored by changes in LC(50) concentrations of the metals, changed from 6.07 microg/L, 12.42 microg/L and 493.32 microg/L to 4.45 microg/L, 25.02 microg/L and 516.69 microg/L, respectively, after three generations of exposure. The metal-selected strains had a significantly lower magnitude of egg viability, larval and pupal survivorship, adult emergence, fecundity and net reproductive rate than the control strain. The population doubling times were significantly longer and the instantaneous birth rates lower in most metal-selected strains relative to the control strain. Our results suggest that although An. gambiae s.s. displays the potential to develop tolerance to heavy metals, particularly copper, this may occur at a significant biological cost, which can adversely affect its ecological fitness.

Additive vs non-additive genetic components in lethal cadmium tolerance of Gammarus (Crustacea): novel light on the assessment of the potential for adaptation to contamination.

Questioning the likelihood that populations adapt to contamination is critical for ecotoxicological risk assessment. The appraisal of genetic variance in chemical sensitivities within populations is currently used to evaluate a priori this evolutionary potential. Nevertheless, conclusions from this approach are questionable since non-additive genetic components in chemical tolerance could limit the response of such complex phenotypic traits to selection. Coupling quantitative genetics with ecotoxicology, this study illustrates how the comparison between cadmium sensitivities among Gammarus siblings enabled discrimination between genetic variance components in chemical tolerance. The results revealed that, whereas genetically determined differences in lethal tolerance exist within the studied population, such differences were not significantly heritable since genetic variance mainly relied on non-additive components. Therefore the potential for genetic adaptation to acute Cd stress appeared to be weak. These outcomes are discussed in regard to previous findings for asexual daphnids, which suggest a strong potency of genetic adaptation to environmental contamination, but which contrast with compiled field observations where adaptation is not the rule. Hereafter, we formulate the reconciling hypothesis of a widespread weakness of additive components in tolerance to contaminants, which needs to be further tested to gain insight into the question of the likelihood of adaptation to contamination.

The incidence and management of tolerance in intrathecal baclofen therapy.

STUDY DESIGN: Retrospective study. OBJECTIVES: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. METHODS: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. RESULTS: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (P<0.05), and then stabilized around a mean dose of 350 microg per day. Eight patients (22%) developed tolerance, defined as a dose increase of >100 microg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance. Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n=11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pump-related complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. CONCLUSIONS: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.

No evidence for the development of acute tolerance to analgesic, respiratory depressant and sedative opioid effects in humans.

It is widely accepted that chronic opioid therapy is associated with the development of pharmacological tolerance. More controversial is the question as to whether acute opioid administration can result in "acute tolerance." The aim of this double-blind, placebo-controlled study in thirty-six healthy human volunteers was to examine whether a 3-h intravenous infusion delivering two different but clinically relevant doses of the mu-opioid receptor agonist remifentanil would result in tolerance to analgesic, respiratory depressant and/or sedative opioid effects. The blood remifentanil concentration versus opioid effect relationship was determined before and after the 3-h infusion. Tolerance was inferred if the potency of remifentanil was significantly lower after the 3-h infusion. Opioid analgesia was assessed with the aid of the cold pressor test and models of electrical and heat pain. Respiratory depression was assessed by measuring arterial pCO2 and minute ventilation. Subjective sedation scores were assessed on a visual analogue scale. Mixed effects modeling was used to relate the steady-state blood remifentanil concentration to each pharmacodynamic assessment. Neither dose of remifentanil produced detectable tolerance to any of the measured opioid effects following a 3-h infusion. The study was adequately powered to detect a decrease in potency of 5-24% for analgesia, 20-48% for respiratory depression, and 32% for sedative effects. These results suggest that short-term administration of clinically useful doses of remifentanil is not associated with the development of significant tolerance to analgesic, respiratory depressant, or sedative opioid effects.

PKCepsilon regulates behavioral sensitivity, binding and tolerance to the CB1 receptor agonist WIN55,212-2.

The cannabinoid CB1 receptor (CB1) is one of the most abundant G protein-coupled receptors in the brain, but little is known about the mechanisms that modulate CB1 receptor signaling. Here, we show that inhibition or null mutation of the epsilon isozyme of protein kinase C (PKCepsilon) selectively enhances behavioral responses to the CB1 agonist WIN55,212-2 in mice, but not to the structurally unrelated CB1 agonist CP55,940. Binding affinity for [(3)H] WIN55,212-2 was increased in brain membranes from PKCepsilon(-/-) mice compared with PKCepsilon(+/+) mice. There was no difference in binding of the inverse agonist [(3)H] SR141716A. In addition, repeated administration of WIN55,212-2 produced greater analgesic and thermal tolerance in PKCvarepsilon(-/-) mice compared with PKCepsilon(+/+)mice. These results indicate that PKCvarepsilon selectively regulates behavioral sensitivity, CB1 receptor binding and tolerance to WIN55,212-2.

Different acute tolerance development to EEG, psychomotor performance and subjective assessment effects after two intermittent oral doses of alprazolam in healthy volunteers.

BACKGROUND/AIMS: Benzodiazepines (BZDs) are the most effective of the psychotropic drugs in the treatment of anxiety disorders. Tolerance has been reported for the majority of BZDs after chronic administration. However, little attention has been paid to the possibility that tolerance might be present after the intermittent oral administration of BZDs. The objectives of the present study were to assess tolerance development after the administration of two intermittent single oral doses of alprazolam given 15 days apart in healthy volunteers, and to compare the results obtained using measures from different domains: neurophysiological, psychomotor and subjective. METHODS: Twenty-four healthy volunteers received 2 mg of alprazolam orally on two experimental days, 15 days apart. Plasma concentrations and pharmacodynamics (PD) were assessed before drug intake and at different times in the following 24 h. PD was assessed through EEG (relative alpha and relative beta-1 activities), cancellation task (total and correct number of responses) and visual analogue scales (activity and drowsiness). RESULTS: No differences were observed in the PKs of alprazolam between occasions. A proteresis was present in both administrations for impairments of psychomotor performance and relative beta-1 activity, whereas it was present only after the second administration for subjective assessments and relative alpha activity. The proteresis on the second occasion was higher than on the first one. CONCLUSIONS: The administration of two single oral doses of alprazolam, 2 weeks apart in healthy volunteers, yielded the same PKs on both occasions, but significant changes were observed in the PD profile. Acute tolerance was observed after the second administration. Two patterns of acute tolerance development were obtained: (1) impairments of psychomotor performance and relative beta-1 activity, and (2) subjective assessments and relative alpha activity.

Short-term metabolic ethanol tolerance in dogs.

Metabolic ethanol tolerance was studied in a cohort of five dogs with ethanol challenge repeated weekly over a 7-week period. During the 7-week period, the area under the blood alcohol versus time curve (AUC) increased slightly while the rate of ethanol elimination also increased slightly. During the repeated ethanol dosing, ethanol absorption shifted from approximately equal absorption in the stomach and intestine to three-fold more absorption in the intestine than in the stomach. The likely cause of the shift in absorption site was probably a concomitant change in gastric emptying that occurred with repeated dosing. This shift is significant since ethanol absorption in the small intestine has been shown to be over six-fold more rapid than ethanol absorption in the stomach.

Untangling ligand induced activation and desensitization of G-protein-coupled receptors.

Long-term treatment with a drug to a G-protein-coupled receptor (GPCR) often leads to receptor-mediated desensitization, limiting the therapeutic lifetime of the drug. To better understand how this therapeutic window might be controlled, we created a mechanistic Monte Carlo model of the early steps in GPCR signaling and desensitization. Using this model we found that the rates of G-protein activation and receptor phosphorylation can be partially decoupled by varying the drug-receptor dissociation rate constant, k(off), and the drug's efficacy, alpha. The maximum ratio of G-protein activation to receptor phosphorylation (GARP) was found for drugs with an intermediate k(off) value and small alpha-value. Changes to the cellular environment, such as changes in the diffusivity of membrane molecules and the G-protein inactivation rate constant, affected the GARP value of a drug but did not change the characteristic shape of the GARP curve. These model results are examined in light of experimental data for a number of GPCRs and are found to be in good agreement, lending support to the idea that the desensitization properties of a drug might be tailored to suit a specific application.

Therapeutic strategies in the choice of antiepileptic drugs.

The choice of treatment of newly diagnosed epilepsy involves many factors such as age, sex, life style, general health and concomitant medication. The seizure type, syndrome, and the pharmacology, efficacy and safety of the antiepileptic drugs (AEDs) should also be considered. Some of the new AEDs appear to provide at least equivalent efficacy with better tolerability. Some of these drugs have the potential to become drugs of first choice in newly diagnosed epilepsy. At the present time, we also must consider the criteria of reimbursement of these drugs. In this paper, we try to describe common and practical strategies to start a treatment of newly diagnosed epilepsy.

Comparison of the cost-effectiveness of milnacipran (a SNRI) with TCAs and SSRIs: a modeling approach.

A simulation model based on the theory of clinical decision analysis was used to compare outcomes and costs when treating patients with major depressive episodes using either a selective serotonin re-uptake inhibitor (SSRI) or a tricyclic antidepressant (TCA), in comparison with milnacipran (a serotonin), and a norepinephrine re-uptake inhibitor (SNRI). The clinical data used were taken from published meta-analyses. This analysis supports: (1) a comparable efficacy of milnacipran and TCA with a better tolerance; and, (2) an advantage of milnacipran over SSRI for efficacy with a comparable tolerance. Based on these findings, a decision tree was constructed with the assistance of a panel of psychiatrists in order to provide a model of usual clinical practice. Estimates not available from clinical studies were obtained either from literature analysis or from the panel. Economic appraisal was performed according to the viewpoint of the French national sickness fund (sécurité sociale), and expenditure assessment was limited to direct costs (hospitalizations, antidepressant medications, visits, and laboratory tests). The results suggest that milnacipran is a cost-effective alternative: the expected cost of treatment per depressive episode is lower than either a French representative panel of TCAs (a saving of 288 FF), or SSRIs (a savings of 961 FF). The expected length of clinical remission is slightly higher than comparators. The robustness of these findings was supported by sensitivity analyses.

Optimal medication use in elders. Key to successful aging.

Pharmacotherapy represents one of the most important ways in which the practice of geriatric medicine differs from conventional medical care. The older patients is a major consumer of prescription and nonprescription medications, and proper use of these agents can lead to more cost-effective strategies in reaching optimal health. A key difference in distinguishing appropriate from inappropriate drug use is evident in the themes of polymedicine and polypharmacy. Polymedicine describes the use of medications for an older population for the treatment of multiple co-morbid conditions, while polypharmacy represents a less-than-desirable state with duplicative medications, drug-to-drug interactions, and inadequate attention to pharmacokinetic and pharmacodynamic principles. The purpose of this paper is to outline strategies toward optimal medication use as a key to successful aging. Specifically, we discuss themes of cost-effective prescribing, the role of medication compliance, overuse and underuse of medication, over-the-counter products, alcohol abuse, and preventive medicine. In addition, we discuss policy implications and responsibility for ensuring the high quality of pharmaceutical care. The reader should have a practical understanding of the pertinent issues in geriatric clinical pharmacology and its relationship to successful aging.