BACKGROUND:

Abuse of heroin and prescription opiate medications has grown to disturbing levels. Opioids mediate their effects through mu opioid receptors (MOR), but minimal information exists regarding MOR-related striatal signaling relevant to the human condition. The striatum is a structure central to reward and habitual behavior and neurobiological changes in this region are thought to underlie the pathophysiology of addiction disorders.

METHODS:

We examined molecular mechanisms related to MOR in postmortem human brain striatal specimens from a homogenous European Caucasian population of heroin abusers and control subjects and in an animal model of heroin self-administration. Expression of ets-like kinase 1 (ELK1) was examined in relation to polymorphism of the MOR gene OPRM1 and drug history.

RESULTS:

A characteristic feature of heroin abusers was decreased expression of MOR and extracellular regulated kinase signaling networks, concomitant with dysregulation of the downstream transcription factor ELK1. Striatal ELK1 in heroin abusers associated with the polymorphism rs2075572 in OPRM1 in a genotype dose-dependent manner and correlated with documented history of heroin use, an effect reproduced in an animal model that emphasizes a direct relationship between repeated heroin exposure and ELK1 dysregulation. A central role of ELK1 was evidenced by an unbiased whole transcriptome microarray that revealed ~20% of downregulated genes in human heroin abusers are ELK1 targets. Using chromatin immune precipitation, we confirmed decreased ELK1 promoter occupancy of the target gene Use1.

CONCLUSIONS:

ELK1 is a potential key transcriptional regulatory factor in striatal disturbances associated with heroin abuse and relevant to genetic mutation of OPRM1.

The use of opioids for migraine is still controversial. Evidence-based guidelines do not recommend opioids as first-line treatment of migraine attacks, while clinical and epidemiological surveys demonstrate that the use of opioids is associated with more severe headache-related disability, symptomology and comorbidities, and greater health-care resource utilization. There are concerns that opioids may be misused or abused, leading to opioid abuse or dependence and migraineurs are particularly prone and at risk for the development of chronic daily headache from opioids overuse. Since clinical and preclinical studies evidence a pathophysiological role of opioids in migraine progression, opioids should be avoided in migraine patients.

The use of opioids in headache treatment is very controversial. In the migraine acute attack use of short-acting opioids is not recommended by the principal guidelines but is frequent in North American emergency departments. Their efficacy in migraine acute attack has not been extensively studied but seems to be similar to non-steroidal anti-inflammatory drugs and metoclopramide. Opioids have been never compared to triptans. The principal concerns about the use of opioids regard the possible association with an increased risk of medication-overuse headache and chronic migraine and the risk of abuse and dependence. These risks have to be considered but not overestimated. The association between frequent use and increased risk of chronic migraine has been observed for almost all categories of acute migraine attack drugs. Compared to the reference category of acetaminophen, risk of chronic migraine for opioid use is only moderately higher (with an OR = 1.48). In some cases, when treatment with triptans, non-steroidal anti-inflammatory drugs, or ergotamines is contraindicated or simply ineffective, a judicious prescription of a short-acting opioid for severe migraine attacks can be considered. Chronic migraine is a highly disabling condition. Although the options for prophylaxis therapy of migraine have expanded and improved considerably over recent years, chronic migraine remains very difficult to treat. The results coming from small clinical series are described, suggesting that in expert hands daily long-acting opioids provide an option for the treatment of some individuals with chronic intractable headaches.

OBJECTIVES

To assess differences in prescription monitoring program (PMP) use between two states with different PMP accessibility (Connecticut [CT] and Rhode Island [RI]), to explore use of PMPs in pharmacy practice, and to examine associations between PMP use and pharmacists' responses to suspected diversion or "doctor shopping." DESIGN Descriptive nonexperimental study. SETTING CT and RI from March through August 2011. PARTICIPANTS Licensed pharmacists in CT and RI. INTERVENTION Anonymous surveys e-mailed to pharmacists MAIN OUTCOME MEASURES PMP use, use of patient reports in pharmacy practice, and responses to suspected doctor shopping or diversion.

RESULTS

Responses from 294 pharmacists were received (CT: 198; RI: 96). PMP users were more likely to use the PMP to detect drug abuse (CT: 79%; RI: 21.9%; P < 0.01) and doctor shopping (67%; 7%; P < 0.01). When faced with suspicious medication use behavior, PMP users were less likely than nonusers to discuss their concerns with the patient (adjusted odds ratio 0.48 [95% CI 0.25-0.92]) but as likely to contact the provider (0.86 [0.21-3.47]), refer the patient back to the prescriber (1.50 [0.79-2.86]), and refuse to fill the prescription (0.63 [0.30-1.30]). PMP users were less likely to state they were out of stock of the drug (0.27 [0.12-0.60]) compared with nonusers. Pharmacists reported high interest in attending continuing education on safe dispensing (72.8%).

CONCLUSION

Pharmacists are important participants in the effort to address prescription drug misuse and abuse. Current PMP use with prevailing systems had limited influence on pharmacy practice. Findings point to future research and needed practice and education innovations to improve patient safety and safer opioid dispensing for pharmacists.

Chronic daily administration of nicotine and other drugs of abuse has been found to entrain pre- and post-drug circadian locomotor activity episodes that oscillate on a 24-h schedule and persist for several days after administration ceases. This drug-entrainable oscillator system could conceivably lead to circadian rhythms of drug seeking and drug use in human drug addicts. The present study (1) characterizes the ability of daily nicotine administration to entrain circadian wheel-running activity episodes in rats across a range of doses, lighting schedules, and food access; and (2) tests whether pre- and post-nicotine episodes can be altered through pharmacological manipulations. Adult female rats were housed in wheel boxes for 35-60 d, and both wheel-running and feeding-related behaviors were measured continuously. Following acclimation, nicotine or saline was administered for 16-24 d, and the rats were left undisturbed for several test days to observe the persistence of nicotine-entrained activity. The results showed that nicotine dose-dependently entrains wheel-running activity, and the highest dose of 1.0 mg/kg produces robust pre- and post-nicotine circadian activity episodes under constant, fixed, and variable light/dark schedules. In the pharmacological manipulation experiment, nicotine-entrained rats were administered one of seven pharmacological treatments (varenicline, mecamylamine, acamprosate, topiramate, naltrexone, SB-334867, or bupropion) in place of the nicotine injection for 2 d, and the rats were not disturbed for four subsequent days. Most of the treatment drugs significantly reduced post-nicotine activity episodes, but only three treatments affected pre-nicotine episodes: the μ- and κ-opioid receptor antagonist naltrexone, the orexin-1 receptor antagonist SB-334867, and the AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid)/kainate antagonist topiramate. These results show that chronic daily nicotine administration is a robust zeitgeber that dose-dependently entrains a nonphotic oscillator system that includes opioid, orexin, and glutamate pathways.

Tamper-resistant formulations (TRFs) of oral opioid drugs are intended to prevent certain types of abuse (eg, intranasal, intravenous). Patients raising objections to receiving a TRF may have valid concerns or may be seeking a formulation that can be more easily misused.US clinicians experienced in pain management met in October 2011 to discuss common patient objections to being switched from a non-TRF opioid to a TRF of the same opioid. Retail pharmacy, health insurance, and scientific data were used to assess the potential validity of these patient objections.Clinical experience switching patients from a non-TRF to a TRF opioid was limited to oxycodone controlled release (CR), as it was the only TRF available at that time; knowledge of other TRFs was limited to the scientific literature. Common objections from patients included "costs more," "not covered by insurance," "can't feel it working," and "causes adverse events." Objective retail pharmacy and insurance coverage information for oxycodone CR was accessible and indicated that patient objections were based on cost and coverage varied by insurer. Unpublished trial results (ClinicalTrials.gov) revealed that TRF oxycodone CR has a slower initial release than the non-TRF formulation, which may reduce positive subjective effects. The complaint "I can't feel it working" may reflect lessened positive subjective effects rather than reduced analgesic efficacy. Most tolerability complaints lacked objective support.The general process used to assess the validity of patient objections to TRF oxycodone CR may be applied to other TRFs once they become available. Publication of clinical data on TRFs would help clinicians to appropriately weigh patient concerns.

Appropriate management of patients in pain clinics can be complex and sometimes confusing because providers must correctly interpret multiple sources of patient information. The correct interpretation of laboratory results is essential to guide subsequent patient treatment and management; however, laboratory and clinical pictures can appear to be conflicting in cases of substance abuse. Incorrect interpretation of laboratory results can multiply negative impacts on clinical outcomes and may lead to patient harm or death. This report introduces the complex nature involved in understanding and interpreting urine drug testing (UDT) results in pain patients who are prescribed opioid medications. Laboratory testing examples of UDT results are provided to illustrate the sometimes discordant nature of UDT interpretation. This case study describes one method of approaching cases where laboratory result interpretation in pain clinic patients is essential for medical treatment and management. The case presented in this manuscript illustrates a reconciliation of an opiate positive immunoassay result in a patient who was prescribed only OxyContin and Wellbutrin after traumatic amputations.