How prevalent and severe is addiction on GABAmimetic drugs in an elderly German general hospital population? Focus on gabapentinoids, benzodiazepines, and z-hypnotic drugs.

OBJECTIVE: Gabapentinoids (GPT) are reported to be increasingly misused by opioid- and polydrug-users, but the addictive potential of GPT outside of these populations remains understudied. Investigations comparing GPT abuse and dependence liability to that of other commonly prescribed Central Nervous System-acting medications are therefore warranted. We provide a comparison of GPT-abuse/dependence to that of other GABAmimetics within an elderly population. DESIGN: DSM-IV-TR-based data (previously prospectively collected by SKID-I-interview) from a random sample of elderly patients admitted to a metropolitan German general hospital were reviewed. The prevalence and severity of GPT, benzodiazepine (BDZ), and z-hypnotic drug (ZD)-abuse and -dependence were compared, stratified also by mono-substance (no concurrent current or previous substance use) and de novo-substance (first)-abuse and -dependence states. RESULTS: Among 400 patients (75 ± 6.4 years old; 63% females), neither current nor past abuse of BDZ, ZD or GPT, nor other illicit substances was observed. Dependence upon BDZ, ZD or GPT was observed among 55 (13.75%) individuals. The related lifetime/12-month prevalence-rates were: dependence condition (BDZ: 7%/2.45%; ZD: 4.25%/4.25%; GPT: 2.75/2.5%); mono-dependence condition (BDZ: 2.25%/0.75%; ZD: 1%/1%, GPT: 0%/0%); de novo-dependence condition (BDZ: 2.75%/1.75%; ZD: 1%/1%, GPT: 0.5%/0.5%). Opioid analgesic-dependence (N = 43/400) was significantly more frequently linked with BDZ than with GPT (p < 0.01) [Correction added on 29 December 2021, after first online publication: In the sentence 'Opioid analgesic-dependence…', the term 'and ZD' has been deleted]. For all three GABAmimetic classes, most mono- and de novo-dependence states were mild-to-moderate and lasted 2-6 years (median). CONCLUSION: GABAmimetic-dependence was usually mixed with other substance-dependences. Every third to fourth instance of BDZ- or ZD-dependence was a mono-dependence condition, while a pure GPT-dependence was absent in this elderly (and illicit substance-naïve) population.

Oxycodone's Unparalleled Addictive Potential: Is it Time for a Moratorium?

PURPOSE OF REVIEW: This study and literature review were carried out to investigate whether oxycodone is the most addictive prescription opioid. RECENT FINDINGS: This was a cross-sectional survey from a pain management practice in south-central Alaska and review of the literature involving 86 patients diagnosed with opioid dependence/opioid use disorder from 2013 to 2018. Patients were given a list of prescription opioids and asked to identify the one (1) most desirable to themselves, (2) most desirable among drug-using associates or community, and (3) they deemed most addictive. Patients with a history of heroin use were asked which, if any, served as their gateway drug to heroin. The literature was reviewed using a PubMed search for articles containing the words "oxycodone" and "abuse," "addiction," "dependence," "disorder," and "euphoria." Oxycodone was ranked most highly in all four questions (n = 50, 60.2%; n = 46, 75.4%; n = 38, 60.2%; n = 14, 77.8%, respectively) by a wide margin. Numerous observational studies performed over the past few decades have demonstrated the supreme "likability" and abuse and dependence liability/addictiveness of oxycodone, with more recent mechanistic studies illuminating biological underpinnings including markedly increased active transport across the blood-brain barrier, increased phasic dopaminergism in the ventral tegmental area, nucleus accumbens and related striatal reward centers, and possibly increased kappa opioid receptor-mediated withdrawal dysphoria. Oxycodone possesses pharmacologic qualities that render it disproportionately liable to abuse and addiction and the risks of any long-term prescription outweigh the benefits.

Further evidence of relationship between thiamine blood level and cognition in chronic alcohol-dependent adults: Prospective Pilot Study of an inpatient detoxification with oral supplementation protocol.

BACKGROUND: The relationship between thiamine blood level (TBL) and cognition remains uncertain, including among alcohol-dependent persons (ADP). AIM: To evaluate this relationship during protocol-driven inpatient alcohol detoxification treatment including thiamine supplementation (AD + Th). METHODS: Prospective 3-week study with 100 consecutively admitted detoxification-seeking ADP (47.7 ± 11 years old, 21% females) without superseding comorbidities requiring treatment. TBL and Montreal Cognitive Assessment (MoCA) were measured at admission (t1, pre-AD + Th) and discharge (t3, post-AD + Th). Frontal Assessment Battery (FAB) was performed at t1. AD + Th included abstinence, pharmacological alcohol withdrawal syndrome treatment, and oral thiamine supplementation (200 mg/day for 14 days). Regression and mediation analyses assessed TBL-cognition relationships. RESULTS: We found no cases of Wernicke Encephalopathy (WE) and only one case of thiamine deficiency. Both MoCA and TBL significantly improved across AD + Th (with medium-to-large effect sizes). At t1, TBL significantly predicted MoCA and FAB sum scores (medium effect sizes; extreme and very strong evidence, respectively). The clear TBL-MoCA association disappeared at t3. In multivariate regression and mediation analyses exploring key influential factors of cognition (identified by LASSO regression), the TBL-MoCA interactions did not relevantly change at t1 and t3. Age, serum transaminases, vitamin D levels, drinking-years, and depression score weakly modified the relationship. CONCLUSION: TBL was a robust predictor of pre-detoxification cognitive impairment, and both TBL and cognition improved significantly during AD + Th (including abstinence) in our ADP population, supporting routine thiamine supplementation for ADP, even those at low WE-risk. The TBL-cognition relationship was minimally confounded by age, alcohol-toxicity proxies, mood, and vitamin D levels.

How to wean friends and influence health: Opioid weaning and discontinuation aided by a simple health and wellness coaching program.

OBJECTIVE: To evaluate whether a simple health and wellness coaching (HWC) program embedded within routine clinical practice resulted in improved opioid weaning and discontinuation. DESIGN: Retrospective double cohort study comparing longitudinal opioid use data and numeric pain scale ratings for patients in each group. SETTING: Single noninstitutional subspecialty pain management practice. PARTICIPANTS: Twenty (daily opioid using) patients undergoing a multifo-cal HWC program with integrated pain neuroscience education (PNE) compared to 20 age- and gender-matched (daily opioid using) patients undergoing usual care. INTERVENTION: A systematized series of interactive self-management topics/lessons on basic health topics pertinent to chronic pain, eg, posture, mobility, nutrition, sleep, stress management, and PNE. MAIN OUTCOME MEASURES: Daily morphine milligram equivalents (MMEs) trajectory and discontinuation success (hypothesis and outcome measure formulated before data collection); numeric pain scale rating trajectory (hypothesis and outcome measure formulated after data collection). RESULTS: MME decrease was significantly greater among cases (93.5 percent) than controls (50 percent; p = 0.004) as was discontinuation of opioids (30 percent vs 0). Cases reported decreased longitudinal 10-digit pain scale rating (-0.8) compared to controls (+0.1) without statistical significance. CONCLUSIONS: Providing simple and salient HWC including PNE within pain management can significantly improve opioid weaning and discontinuation while mitigating pain.

Low-dose naltrexone, an opioid-receptor antagonist, is a broad-spectrum analgesic: a retrospective cohort study.

Aim: To evaluate the use of low-dose naltrexone (LDN) as a broad-spectrum analgesic. Methods: Retrospective cohort study from a single pain management practice using data from 2014 to 2020. Thirty-six patients using LDN for ≥2 months were matched to 42 controls. Pain scores were assessed at initial visit and at most recent/final documented visit using a 10-point scale. Results: Cases reported significantly greater pain reduction (-37.8%) than controls (-4.3%; p < 0.001). Whole sample multivariate modeling predicts 33% pain reduction with LDN, with number needed to treat (for 50% pain reduction) of 3.2. Patients with neuropathic pain appeared to benefit even more than those with 'nociceptive'/inflammatory pain. Conclusion: LDN is effective in a variety of chronic pain states, likely mediated by TLR-4 antagonism.

Naltrexone has historically been used to treat various substance use disorders, but recent discoveries have sparked interest in using low-dose naltrexone (LDN) to manage chronic pain. This study compared pain levels reported by patients before and after at least 2 months of LDN treatment to those reported by patients with the same painful diseases, who did not take LDN. Overall, patients who took LDN reported significantly more pain relief than patients who did not take LDN. How LDN alleviates pain seems complex, but apparently involves an anti-inflammatory effect on cells in the brain and spinal cord. LDN is extraordinarily safe, with no known risks (unlike most standard pain medications), and should be studied more in the treatment of chronic pain.

Gabapentinoid Benefit and Risk Stratification: Mechanisms Over Myth.

INTRODUCTION: Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications. RESULTS: Gabapentinoids inhibit the joint action of voltage-gated calcium channel (VGCC) α2δ subunits in conjunction with the n-methyl-D-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and excitatory neurotransmitter release, and possibly synaptogenesis as well, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which explains in part the efficacy of the gabapentinoids in the management of neuropathic pain. Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among central nerve system-acting agents, which is also thought to explain some of the therapeutic benefit of the class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of the nonsteroidal anti-inflammatory drugs, but with a considerably improved safety profile. Along these lines, in the context of over 50 million prescriptions per year in the USA alone, the gabapentinoids display remarkably low risk, including risks of misuse, abuse, and dependence. Furthermore, the neurobiology of these agents does not lend plausibility to the allegations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and in addition likely confer a "negative-feedback loop" for habituation and dependence by serving as functional NMDA antagonists, possibly through their actions on thrombospondins. Clinical and epidemiological addictionology studies corroborate the lack of any significant addictive potential of the gabapentinoids, and these drugs are increasingly being used in the treatment of addiction to other substances, with excellent results and no evidence of cross-addiction. However, among individuals with other substance use disorders and, in particular opioid use disorder, there are consistent data showing misuse of gabapentinoids in up to 20% of this population. Although there are allegations of using gabapentinoids to amplify the hedonic effects of opioids, the vast majority of misuse events appear to occur in an attempt to ameliorate opioid withdrawal symptoms. Furthermore, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use. Careful risk:benefit assessment and stratification are warranted when prescription of a gabapentinoid is under consideration, in particular among individuals using opioids. CONCLUSIONS: Gabapentinoids remain a vital tool in the pain physician's multimodal armamentarium, but these drugs may not be effective in every clinical situation. Individuals with central sensitization and pain associated with slow-wave sleep deficits and potentially persons with comorbid addictions may benefit the most. The gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but they may be abused by persons with opioid use disorders; consequently, cautious risk stratification must take place.

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

Background: For cannabis-dependent subjects, the relationship between cannabis withdrawal syndrome (CWS) severity and the urine cannabinoid concentrations are unclear; we investigated this using a commercial point-of-care (POC) enzyme immunoassay detecting 11-nor-9-carboxy-Delta-9-tetrahydrocannabinol (THC-COOH). Methods: Observational study of 78 adult chronic cannabis-dependent subjects assessed over a 24-day inpatient detoxification treatment, with 13 serial measurement days. Repeated Measures Correlation and Multilevel Linear Models were employed. Results: Absolute urinary THC-COOH levels significantly correlated with Marijuana Withdrawal Checklist (MWC) scores across the entire study duration (r = 0.248; p < 0.001). Correlation between serial creatinine-adjusted THC-COOH ratios and serial MWC scores emerged as significant only in the sample with higher MWC scores (>11 points) at admission (n = 21; r = 0.247; p = 0.002). The aforementioned significant relationships have persisted when replacing the absolute THC-COOH-levels with the (relative) day-to-day change in urinary THC-COOH levels. MWC scores were significantly correlated with the Clinical Global Impression-Severity (CGI-S; r = 0.812; p < 0.001). Females showed a significantly slower decline in urine THC-COOH levels and prolonged CWS course characterized by substantial illness severity (per CGI-S), occurring in nearly 30% of cases. Conclusion: Urine cannabinoid levels (THC-COOH) determined by POC assay significantly predicted CWS severity (moderate correlation), guiding detoxification treatment duration. In patients with MWC > 11 points upon admission, creatinine-adjusted THC-COOH ratios also significantly predicted CWS severity-again with moderate effect size. Females showed prolonged urinary THC-COOH elimination and cannabis withdrawal.

Ranking the Harm of Psychoactive Drugs Including Prescription Analgesics to Users and Others-A Perspective of German Addiction Medicine Experts.

Background: Over the past 15 years, comparative assessments of psychoactive substance harms to both users and others have been compiled by addiction experts. None of these rankings however have included synthetic cannabinoids or non-opioid prescription analgesics (NOAs, e.g., gabapentinoids) despite evidence of increasing recreational use. We present here an updated assessment by German addiction medicine experts, considering changing Western consumption trends-including those of NOAs. Methods: In an initial survey, 101 German addiction medicine physicians evaluated both physical and psychosocial harms (in 5 dimensions) of 33 psychoactive substances including opioids and NOAs, to both users and others. In a second survey, 36 addiction medicine physicians estimated the relative weight of each health and social harm dimension to determine the overall harm rank of an individual substance. We compared our ranking with the most recent European assessment from 2014. Results: Illicit drugs such as methamphetamine, heroin, cocaine and also alcohol were judged particularly harmful, and new psychoactive drugs (cathinones, synthetic cannabinoids) were ranked among the most harmful substances. Cannabis was ranked in the midrange, on par with benzodiazepines and ketamine-somewhat more favorable compared to the last European survey. Prescribed drugs including opioids (in contrast to the USA, Canada, and Australia) were judged less harmful. NOAs were at the bottom end of the ranking. Conclusion: In Germany, alcohol and illicit drugs (including new psychoactive substances) continue to rank among the most harmful addictive substances in contrast to prescribed agents including opioid analgesics and NOAs. Current laws are incongruent with these harm rankings. This study is the first of its kind to include comparative harm rankings of several novel abused substances, both licit/prescribed and illicit.

Rationale for and approach to preoperative opioid weaning: a preoperative optimization protocol.

The practice of chronic opioid prescription for chronic non-cancer pain has come under considerable scrutiny within the past several years as mounting evidence reveals a generally unfavorable risk to benefit ratio and the nation reels from the grim mortality statistics associated with the opioid epidemic. Patients struggling with chronic pain tend to use opioids and also seek out operative intervention for their complaints, which combination may be leading to increased postoperative "acute-on-chronic" pain and fueling worsened chronic pain and opioid dependence. Besides worsened postoperative pain, a growing body of literature, reviewed herein, indicates that preoperative opioid use is associated with significantly worsened surgical outcomes, and severely increased financial drain on an already severely overburdened healthcare budget. Conversely, there is evidence that preoperative opioid reduction may result in substantial improvements in outcome. In the era of accountable care, efforts such as the Enhanced Recovery After Surgery (ERAS) protocol have been introduced in an attempt to standardize and facilitate evidence-based perioperative interventions to optimize surgical outcomes. We propose that addressing preoperative opioid reduction as part of a targeted optimization approach for chronic pain patients seeking surgery is not only logical but mandatory given the stakes involved. Simple opioid reduction/abstinence however is not likely to occur in the absence of provision of viable and palatable alternatives to managing pain, which will require a strong focus upon reducing pain catastrophization and bolstering self-efficacy and resilience. In response to a call from our surgical community toward that end, we have developed a simple and easy-to-implement outpatient preoperative optimization program focusing on gentle opioid weaning/elimination as well as a few other high-yield areas of intervention, requiring a minimum of resources.

Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.

BACKGROUND: Opioid use, abuse, and adverse consequences, including death, have escalated at an alarming rate since the 1990s. In an attempt to control opioid abuse, numerous regulations and guidelines for responsible opioid prescribing have been developed by various organizations. However, the US opioid epidemic is continuing and drug dose deaths tripled during 1999 to 2015. Recent data show a continuing increase in deaths due to natural and semisynthetic opioids, a decline in methadone deaths, and an explosive increase in the rates of deaths involving other opioids, specifically heroin and illicit synthetic fentanyl. Contrary to scientific evidence of efficacy and negative recommendations, a significant proportion of physicians and patients (92%) believe that opioids reduce pain and a smaller proportion (57%) report better quality of life. In preparation of the current guidelines, we have focused on the means to reduce the abuse and diversion of opioids without jeopardizing access for those patients suffering from non-cancer pain who have an appropriate medical indication for opioid use. OBJECTIVES: To provide guidance for the prescription of opioids for the management of chronic non-cancer pain, to develop a consistent philosophy among the many diverse groups with an interest in opioid use as to how appropriately prescribe opioids, to improve the treatment of chronic non-cancer pain and to reduce the likelihood of drug abuse and diversion. These guidelines are intended to provide a systematic and standardized approach to this complex and difficult arena of practice, while recognizing that every clinical situation is unique. METHODS: The methodology utilized included the development of objectives and key questions. The methodology also utilized trustworthy standards, appropriate disclosures of conflicts of interest, as well as a panel of experts from various specialties and groups. The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed, with a best evidence synthesis of the available literature, and utilized grading for recommendation as described by the Agency for Healthcare Research and Quality (AHRQ).Summary of Recommendations:i. Initial Steps of Opioid Therapy 1. Comprehensive assessment and documentation. (Evidence: Level I; Strength of Recommendation: Strong) 2. Screening for opioid abuse to identify opioid abusers. (Evidence: Level II-III; Strength of Recommendation: Moderate) 3. Utilization of prescription drug monitoring programs (PDMPs). (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 4. Utilization of urine drug testing (UDT). (Evidence: Level II; Strength of Recommendation: Moderate) 5. Establish appropriate physical diagnosis and psychological diagnosis if available. (Evidence: Level I; Strength of Recommendation: Strong) 6. Consider appropriate imaging, physical diagnosis, and psychological status to collaborate with subjective complaints. (Evidence: Level III; Strength of Recommendation: Moderate) 7. Establish medical necessity based on average moderate to severe (≥ 4 on a scale of 0 - 10) pain and/or disability. (Evidence: Level II; Strength of Recommendation: Moderate) 8. Stratify patients based on risk. (Evidence: Level I-II; Strength of Recommendation: Moderate) 9. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: Level I-II; Strength of Recommendation: Moderate) 10. Obtain a robust opioid agreement, which is followed by all parties. (Evidence: Level III; Strength of Recommendation: Moderate)ii. Assessment of Effectiveness of Long-Term Opioid Therapy 11. Initiate opioid therapy with low dose, short-acting drugs, with appropriate monitoring. (Evidence: Level II; Strength of Recommendation: Moderate) 12. Consider up to 40 morphine milligram equivalent (MME) as low dose, 41 to 90 MME as a moderate dose, and greater than 91 MME as high dose. (Evidence: Level II; Strength of Recommendation: Moderate) 13. Avoid long-acting opioids for the initiation of opioid therapy. (Evidence: Level I; Strength of Recommendation: Strong) 14. Recommend methadone only for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses, within FDA recommended doses. (Evidence: Level I; Strength of Recommendation: Strong) 15. Understand and educate the patients of the effectiveness and adverse consequences. (Evidence: Level I; Strength of Recommendation: Strong) 16. Similar effectiveness for long-acting and short-acting opioids with increased adverse consequences of long-acting opioids. (Evidence: Level I-II; Strength of recommendation: Moderate to strong) 17. Periodically assess pain relief and/or functional status improvement of ≥ 30% without adverse consequences. (Evidence: Level II; Strength of recommendation: Moderate) 18. Recommend long-acting or high dose opioids only in specific circumstances with severe intractable pain. (Evidence: Level I; Strength of Recommendation: Strong)iii. Monitoring for Adherence and Side Effects 19. Monitor for adherence, abuse, and noncompliance by UDT and PDMPs. (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 20. Monitor patients on methadone with an electrocardiogram periodically. (Evidence: Level I; Strength of Recommendation: Strong). 21. Monitor for side effects including constipation and manage them appropriately, including discontinuation of opioids when indicated. (Evidence: Level I; Strength of Recommendation: Strong)iv. Final Phase 22. May continue with monitoring with continued medical necessity, with appropriate outcomes. (Evidence: Level I-II; Strength of Recommendation: Moderate) 23. Discontinue opioid therapy for lack of response, adverse consequences, and abuse with rehabilitation. (Evidence: Level III; Strength of Recommendation: Moderate) CONCLUSIONS: These guidelines were developed based on comprehensive review of the literature, consensus among the panelists, in consonance with patient preferences, shared decision-making, and practice patterns with limited evidence, based on randomized controlled trials (RCTs) to improve pain and function in chronic non-cancer pain on a long-term basis. Consequently, chronic opioid therapy should be provided only to patients with proven medical necessity and stability with improvement in pain and function, independently or in conjunction with other modalities of treatments in low doses with appropriate adherence monitoring and understanding of adverse events.Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversionDisclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."