PubMed Update: Another Year in Overdose

Another year in overdose, September 2012-August 2013, generally in reverse chronological order, and following the same loosely-formed categories as last year.

Once again, this is opioid focused and misses anything not listed in the PubMed database – which means it misses many interesting papers to which you are warmly welcomed to post links!

This year there were 99 papers, up from 81 in the preceding 12 months.

1) Notes from the field: acetyl fentanyl overdose fatalities – rhode island, march-may 2013.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2013 Aug 30;62(34):703-4.

Comment: The evidence of synthetic fentanyl was difficult to detect and concerning to many as heralding a possible repeat of the 2006/2007 fentanyl-tainted heroin overdose outbreak.

2) Cory monteith dies of a heroin overdose at age 31.

Willens JS.

Pain Manag Nurs. 2013 Sep;14(3):125. doi: 10.1016/j.pmn.2013.07.004. No abstract available.

Comment: The Glee star.

3) Redressing the epidemics of opioid overdose and HIV among people who inject drugs in Central Asia: The need for a syndemic approach.

Gilbert L, Primbetova S, Nikitin D, Hunt T, Terlikbayeva A, Momenghalibaf A, Ruziev M, El-Bassel N.

Drug Alcohol Depend. 2013 Aug 13. doi:pii: S0376-8716(13)00282-2.

Comment: A really interesting approach to thinking about HIV and drug overdose mortality, through the lens of syndemics – a hot topic in public health – and risk environments. With the bonus of an important review of data from several Central Asian states.

4) Associations Between Injection Risk and Community Disadvantage Among Suburban Injection Drug Users in Southwestern Connecticut, USA.

Heimer R, Barbour R, Palacios WR, Nichols LG, Grau LE.

AIDS Behav. 2013 Aug 7. [Epub ahead of print]

Comment: Intriguing paper on rural heroin use.

5) Non-Fatal Opioid Overdose and Major Depression among Street-Recruited Young Heroin Users.

Chahua M, Sordo L, Barrio G, Domingo-Salvany A, Brugal MT, Molist G, de la Fuente L, Bravo MJ.

Eur Addict Res. 2013 Aug 1;20(1):1-7. [Epub ahead of print]

Comment: There haven’t been many overdose studies out of Spain. Nice to see this.

6) [Heroin].

Demaret I, Lemaître A, Ansseau M.

Rev Med Liege. 2013 May-Jun;68(5-6):287-93. French.

Comment: What appears from the abstract to be a nice review for Belgium of heroin addiction.

7) Vital signs: overdoses of prescription opioid pain relievers and other drugs among women–United States, 1999-2010.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2013 Jul 5;62(26):537-42.

Comment: More women have died from drug overdose than motor vehicle accidents in the U.S. since 2007.

8) Non-fatal overdose among adult prisoners with a history of injecting drug use in two Australian states.

Moore E, Winter R, Indig D, Greenberg D, Kinner SA.

Drug Alcohol Depend. 2013 Jul 15. doi:pii: S0376-8716(13)00220-2.

Comments: Survey of prisoners lifetime history of overdose.

9) Methadone-Related Overdose Deaths in Rural Virginia: 1997 to 2003.

Wunsch MJ, Nuzzo PA, Behonick G, Massello W, Walsh SL.

J Addict Med. 2013 Jul 8. [Epub ahead of print]

Comments: Analysis of methadone-related deaths.

10) The Economic Burden of Opioid-Related Poisoning in the United States.

Inocencio TJ, Carroll NV, Read EJ, Holdford DA.

Pain Med. 2013 Jul 10. doi: 10.1111/pme.12183. [Epub ahead of print]

Comments: Intriguing analysis of costs of opioid overdose, focusing on the costs to the healthcare system.

11) Supply-side response to declining heroin purity: fentanyl overdose episode in New Jersey.

Hempstead K, Yildirim EO.

Health Econ. 2013 Jun 6. doi: 10.1002/hec.2937. [Epub ahead of print]

Comment: Fascinating.

12) The relationship between age and risky injecting behaviours among a sample of Australian people who inject drugs.

Horyniak D, Dietze P, Degenhardt L, Higgs P, McIlwraith F, Alati R, Bruno R, Lenton S, Burns L.

Drug Alcohol Depend. 2013 May 9. doi:pii: S0376-8716(13)00116-6. 10.1016/j.drugalcdep.2013.03.021. [Epub ahead of print]

Comments: More excellent work from this team. I particularly appreciate the estimate of the reduction in overdose risk with age. In a mathematical model of overdose, we estimated a 50% reduction in the risk of overdose over 10 years of use, whereas this paper suggests the figure is closer to 20% – data that will be very helpful in future iterations.

13) All-cause mortality in criminal justice clients with substance use problems-A prospective follow-up study.

Hakansson A, Berglund M.

Drug Alcohol Depend. 2013 Apr 24. doi:pii: S0376-8716(13)00109-9. 10.1016/j.drugalcdep.2013.03.014. [Epub ahead of print]

Comments: Another analysis of post-release mortality among prisoners, in which the largest group (39%) of deaths were due to accidental or undetermined intent poisoning.

14) Diversity in causes and characteristics of drug-induced deaths in an urban setting.

Gjersing L, Jonassen KV, Biong S, Ravndal E, Waal H, Bramness JG, Clausen T.

Scand J Public Health. 2013 Mar;41(2):119-25. doi: 10.1177/1403494812472007. Epub 2013 Jan 9.

Comments: Overview of epidemiologic characteristics of 231 overdose deaths in Norway.

15) Determination of substance overdose in two Iranian centers: Comparison between opioids and non-opioids.

Taghaddosinejad F, Arefi M, Fayaz AF, Tanhaeivash R.

J Forensic Leg Med. 2013 Apr;20(3):155-7.

Comment: Interesting exploration of overdose in Iran – opioids still predominate (1782) compared to other drugs (94).

16) Diversity in causes and characteristics of drug-induced deaths in an urban setting.

Gjersing L, Jonassen KV, Biong S, Ravndal E, Waal H, Bramness JG, Clausen T.

Scand J Public Health. 2013 Jan 9. [Epub ahead of print]

Comments: Basic and important epidemiology of drug-related deaths in Oslo. Mostly opioids, lots of contact with social services prior to death.

17) Improvement in the detection of adverse drug events by the use of electronic health and prescription records: An evaluation of two trigger tools.

Nwulu U, Nirantharakumar K, Odesanya R, McDowell SE, Coleman JJ.

Eur J Clin Pharmacol. 2013 Feb;69(2):255-9. doi: 10.1007/s00228-012-1327-1. Epub 2012 Jun 17.

Comments: An intriguing look at electronic record “triggers” to identify adverse events. Administration of naloxone had a positive-predictive value of 91% for opioid overmedication. This is a secondary care setting, not an emergency setting. In an emergency or field setting, such a trigger may still have a high positive predictive value, but the negative predictive value is likely inadequate to justify its use for out-of-hospital overdose detection.

18) Understanding drug-related mortality in released prisoners: a review of national coronial records.

Andrews JY, Kinner SA.

BMC Public Health. 2012 Apr 4;12:270. doi: 10.1186/1471-2458-12-270. Review.

Comment: Almost half of the deaths among ex-prisoners in Australia from 2000-2007 were due to drug overdose, 82% of which demonstrated heroin and/or morphine on toxicology. Those who died of drug-related death were less likely that those who died of other causes to have mental health conditions or a history of self-harm. The were more likely to have a history of heroin use, drug withdrawal, injecting drugs, and drug overdose.

19) Unintentional Prescription Opioid-Related Overdose Deaths: Description of Decedents by Next of Kin or Best Contact, Utah, 2008-2009.

Johnson EM, Lanier WA, Merrill RM, Crook J, Porucznik CA, Rolfs RT, Sauer B.

J Gen Intern Med. 2012 Oct 16. [Epub ahead of print]

Comment: The authors interviewed next of kin or best contacts, a very compelling approach to studying the characteristics of opioid analgesic use resulting in overdose death. About a quarter had a history of heroin use and the vast majority had been to the emergency department previously for problems related to substance use. Over 90% had gotten prescription pain medication from a healthcare provider within the year leading up to their death (prescription database studies have suggested one to two-thirds of deaths are due to drugs prescribed to the decedent, but getting some prescriptions from a healthcare provider does not necessarily mean they received the agent that led to the overdose from a provider).

20) The relationship between alcohol use and injecting drug use: Impacts on health, crime and wellbeing.

Dietze P, Jenkinson R, Aitken C, Stoové M, Jolley D, Hickman M, Kerr T.

Drug Alcohol Depend. 2012 Sep 15. pii: S0376-8716(12)00330-4. doi: 10.1016/j.drugalcdep.2012.08.013. [Epub ahead of print]

Comment: Drug injectors who drink heavily have more violent crime and poorer life satisfaction. Somewhat surprisingly, other health outcomes (like heroin overdose) did not survive controlling for potential confounders.

21) Suicide attempts and overdoses among adults entering addictions treatment: comparing correlates in a U.S. National Study.

Bohnert AS, Roeder KM, Ilgen MA.

Drug Alcohol Depend. 2011 Dec 1;119(1-2):106-12. Epub 2011 Jun 28.

Comment: This is an intriguing analysis of the complex issue of suicide and drug overdose based on a large cross-sectional dataset of substance use treatment patients (N=5892). Twenty percent were in treatment for marijuana, 42% for alcohol, 61% for cocaine, and 19% for heroin. I would be interested in seeing the analysis restricted to those in treatment for heroin, as that is a more homogenous group at higher risk for overdose. Also, while we know that only a small proportion of heroin overdose among heroin users is intentional, an analysis such as this may help to tease apart how much overdose is related to attempts at self-harm.

1) Methadone induced sensorineural hearing loss.

Saifan C, Glass D, Barakat I, El-Sayegh S.

Case Rep Med. 2013;2013:242730. doi: 10.1155/2013/242730. Epub 2013 Jul 29.

Comment: In this case the patient was restarted on methadone and the sensorineural hearing loss was permanent.

2) Methadone toxicity: comparing tablet and syrup formulations during a decade in an academic poison center of Iran.

Shadnia S, Rahimi M, Hassanian-Moghaddam H, Soltaninejad K, Noroozi A.

Clin Toxicol (Phila). 2013 Aug 23. [Epub ahead of print]

Comment: Accidental poisonings among family in Iran for (insufficiently-labeled) take-home methadone syrup.

3) Increased densities of nitric oxide synthase expressing neurons in the temporal cortex and the hypothalamic paraventricular nucleus of polytoxicomanic heroin overdose victims: Possible implications for heroin neurotoxicity.

Bernstein HG, Trübner K, Krebs P, Dobrowolny H, Bielau H, Steiner J, Bogerts B.

Acta Histochem. 2013 Aug 13. doi:pii: S0065-1281(13)00145-1.

Comment: Interesting analysis comparing heroin overdose patients to controls, although I’m unclear it’s direct relationship to the pathologic processes of overdose.

4) Fentanyl-associated fatalities among illicit drug users in Wayne County, Michigan (July 2005-May 2006).

Algren DA, Monteilh CP, Punja M, Schier JG, Belson M, Hepler BR, Schmidt CJ, Miller CE, Patel M, Paulozzi LJ, Straetemans M, Rubin C.

J Med Toxicol. 2013 Mar;9(1):106-15. doi: 10.1007/s13181-012-0285-4.

Comment: A review of pathological details related to the tragic 2005-2007 fentanyl-tainted heroin outbreak.

5) Potential P-glycoprotein Pharmacokinetic Interaction of Telaprevir With Morphine or Methadone.

Fudin J, Fontenelle DV, Fudin HR, Carlyn C, Hinden DA, Ashley CC.

J Pain Palliat Care Pharmacother. 2013 Jul 24. [Epub ahead of print]

Comment: Some potential interactions of the HCV protease inhibitor with selected opioids. Hopefully we won’t be using telaprevir too much longer as more advanced, effective, and easily tolerated regimens are expected as early as the end of 2013.

6) A drug fatality involving Kratom.

Neerman MF, Frost RE, Deking J.

J Forensic Sci. 2013 Jan;58 Suppl 1:S278-9. doi: 10.1111/1556-4029.12009. Epub 2012 Oct 19.

Comments: Kratom is a plant that grows in North America (this case is from Texas) and many other parts of the world. Its use is prohibited in Thailand. It acts as a mu-opioid receptor agonist.

7) Methadone-induced toxic brain damage.

Corré J, Pillot J, Hilbert G.

Case Rep Radiol. 2013;2013:602981. doi: 10.1155/2013/602981. Epub 2013 May 22.

Comment: Cerebellar and basal ganglia damage from methadone overdose.

8) Ethanol Reversal of Cellular Tolerance to Morphine in Rat Locus Coeruleus Neurons.

Llorente J, Withey S, Rivero G, Cunningham M, Cooke A, Saxena K, McPherson J, Oldfield S, Dewey W, Bailey C, Kelly E, Henderson G.

Mol Pharmacol. 2013 May 28. [Epub ahead of print]

Comments: Intriguing analysis of ethanol and morphine, suggesting that alcohol may enhance the effects of morphine. Could this account for some of the risk of combining opioids with alcohol?

9) Hypoglycemia during rapid methadone dose escalation.

Moryl N, Pope J, Obbens E.

J Opioid Manag. 2013 Jan-Feb;9(1):29-34. doi: 10.5055/jom.2013.0144.

Comments: One of a handful of issues with methadone dosing that may have factored into the challenges encountered by providers and patients with this drug when used for pain.

10) Benzodiazepine use during buprenorphine treatment for opioid dependence: Clinical and safety outcomes.

Schuman-Olivier Z, Hoeppner BB, Weiss RD, Borodovsky J, Shaffer HJ, Albanese MJ.

Drug Alcohol Depend. 2013 May 17. doi:pii: S0376-8716(13)00133-6. 10.1016/j.drugalcdep.2013.04.006. [Epub ahead of print]

Comments: For patients on any opioid medications, benzodiazepines are associated with an increased risk of overdose. This study of 328 buprenorphine maintenance patients didn’t find an association with benzodiazepine prescriptions and overdose, but did find an association with more frequent emergency department visits and injury-related ED visits. We may never learn if benzodiazepines are causal in this pathway or merely a marker, but these data do contribute to the overall concern.

11) Determination of dextromethorphan and levomethorphan in seized heroin samples by enantioselective HPLC and electronic CD.

Tedesco D, Di Pietra AM, Rossi F, Garagnani M, Del Borrello E, Bertucci C, Andrisano V.

J Pharm Biomed Anal. 2013 Apr 6;81-82C:76-79. doi: 10.1016/j.jpba.2013.03.024. [Epub ahead of print]

Comment: Methods paper demonstrating methorphan in some heroin samples involved in overdose death.

12) The Toxicology Investigators Consortium Case Registry–the 2011 experience.

Wiegand TJ, Wax PM, Schwartz T, Finkelstein Y, Gorodetsky R, Brent J; Toxicology Investigators Consortium Case Registry Investigators.

J Med Toxicol. 2012 Dec;8(4):360-77. doi: 10.1007/s13181-012-0264-9.

Comments: Interesting analysis of a relatively new dataset including cases evaluated by medical toxicologists from multiple sites. Opioids were a leading issue (although this is a set of referred cases and opioid overdose rarely requires referral, so the contribution of opioids to overdose events should be very much underestimated in this cohort).

13) Methadone toxicity and possible induction and enhanced elimination in a premature neonate.

George M, Kitzmiller JP, Ewald MB, O’Donell KA, Becter ML, Salhanick S.

J Med Toxicol. 2012 Dec;8(4):432-5. doi: 10.1007/s13181-012-0249-8.

Comments: Case report of a massive methadone overdose in a neonate. I can’t access so don’t know if it was iatrogenic.

14) Death Due to Apparent Intravenous Injection of Tapentadol.

Kemp W, Schlueter S, Smalley E.

J Forensic Sci. 2012 Oct 19. doi: 10.1111/j.1556-4029.2012.02299.x. [Epub ahead of print]

Comment: Tapentadol is opioid available by the brand names Nucynta and Palexia.

15) Cognitive skills underlying driving in patients discharged following self-poisoning with central nervous system depressant drugs.

Dassanayake TL, Michie PT, Jones AL, Mallard T, Whyte IM, Carter GL.

Traffic Inj Prev. 2012 Sep;13(5):450-7.

Comment: Interesting paper exploring the persistent impairment in cognitive functioning after drug poisoning. The authors focused on possible residual drug effect, although I do wonder if there is a cognitive impact of non-fatal overdose beyond residual drug effect.

16) Oxycodone overdose causes naloxone responsive coma and QT prolongation.

Berling I, Whyte IM, Isbister GK.

QJM. 2012 Sep 28. [Epub ahead of print]

PMID: 23023890 [PubMed – as supplied by publisher]

Comment: High-dose opioids can cause QT prolongation, a hypothetical bugaboo for methadone maintenance. What is QT prolongation? It is a warning sign that somebody might be at risk for a potentially fatal heart rhythm. More detail, you ask? Well, the EKG is a record of electrical activity in the heart – see below. Some medications make the time from Q to T longer. If it gets long enough (usually requiring very high doses of opioids in combination with either other medications or a genetic tendency to have a long QT) it can result in a dangerous heart rhythm.

17) Delayed posthypoxic leukoencephalopathy: Case reports.

Okuda S, Ueno M, Hayakawa M, Araki M, Kanda F, Takano S.

Rinsho Shinkeigaku. 2012;52(9):672-6.

Comment: Two case reports of a debilitating white matter brain disease from benzodiazepine overdose.

18) Seizures after use and abuse of tramadol.

Bekjarovski N, Chaparoska D, Radulovikj-Bekjarovska S.

Prilozi. 2012 Jul;33(1):313-8.

Comment: Tramadol is an interesting drug, with some opioid-esque effects, but not really an opioid. Seizures can result from tramadol overuse.

19) Sulfation of Buprenorphine, Pentazocine, and Naloxone by Human Cytosolic Sulfotransferases.

Kurogi K, Chen M, Lee Y, Shi B, Yang T, Liu MY, Sakakibara Y, Suiko M, Liu MC.

Drug Metab Lett. 2012 Aug 31. [Epub ahead of print]

Comment: Details on metabolism of naloxone, buprenorphine, and pentazocine.

1) Opioids compared to placebo or other treatments for chronic low-back pain.

Chaparro LE, Furlan AD, Deshpande A, Mailis-Gagnon A, Atlas S, Turk DC.

Cochrane Database Syst Rev. 2013 Aug 27;8:CD004959. doi:

Comment: There are no quality data to support long-term management of non-cancer pain with opioids.

2) Opioid antagonists for pain.

Taylor R Jr, Pergolizzi JV Jr, Porreca F, Raffa RB.

Expert Opin Investig Drugs. 2013 Apr;22(4):517-25. doi: 10.1517/13543784.2013.778973. Review.

Comment: Fascinating paper on the analgesic properties of opioid ANTagonists.

3) Comparison of fatal poisonings by prescription opioids.

Häkkinen M, Launiainen T, Vuori E, Ojanperä I.

Forensic Sci Int. 2012 Oct 10;222(1-3):327-31.

Comment: An interesting analysis that suggests different motivations behind overdose on different opioids (e.g. weaker opioids resulting in death more likely to be intentional/suicidal).

4) Heroin use and heroin use risk behaviors among nonmedical users of prescription opioid pain relievers – United States, 2002-2004 and 2008-2010.

Jones CM.

Drug Alcohol Depend. 2013 Feb 11. doi:pii: S0376-8716(13)00019-7. 10.1016/j.drugalcdep.2013.01.007. [Epub ahead of print]

Comment: Compelling analysis of the pathway from prescription opioid use to heroin use.

5) Prescription opioid use among addictions treatment patients: Nonmedical use for pain relief vs. other forms of nonmedical use.

Bohnert AS, Eisenberg A, Whiteside L, Price A, McCabe SE, Ilgen MA.

Addict Behav. 2012 Nov 23;38(3):1776-1781. doi: 10.1016/j.addbeh.2012.11.005. [Epub ahead of print]

Comments: Survey of prescription opioid use among treatment program patients. Use for reasons other than pain relief was associated with overdose as well as use of several other agents that increase the risk of overdose.

6) Opioid-induced respiratory depression in paediatrics: a review of case reports.

Niesters M, Overdyk F, Smith T, Aarts L, Dahan A.

Br J Anaesth. 2012 Dec 17. [Epub ahead of print]

Comments: Very intriguing review of opioid overdose cases among children, identifying three issues associated with respiratory depression: renal dysfunction, CYP2D6 polymorphism resulting in rapid accumulation of morphine as a codeine metabolite, and obstructive sleep apnea.

7) Fentanyl-associated Fatalities Among Illicit Drug Users in Wayne County, Michigan (July 2005-May 2006).

Algren DA, Monteilh CP, Punja M, Schier JG, Belson M, Hepler BR, Schmidt CJ, Miller CE, Patel M, Paulozzi LJ, Straetemans M, Rubin C.

J Med Toxicol. 2013 Jan 29. [Epub ahead of print]

Comments: An analysis from the fentanyl-laced heroin overdose fatality epidemic that struck the eastern United States from 2005-2007. This epidemic was substantial and deserves mention in any modern history of overdose in North America as it led to the active engagement of several federal agencies in addressing overdose.

8) Prescription opioid mortality trends in New York City, 1990-2006: Examining the emergence of an epidemic.

Cerdá M, Ransome Y, Keyes KM, Koenen KC, Tracy M, Tardiff KJ, Vlahov D, Galea S.

Drug Alcohol Depend. 2013 Jan 25. doi:pii: S0376-8716(13)00003-3. 10.1016/j.drugalcdep.2012.12.027. [Epub ahead of print]

Comments: Interesting analysis of demographic characteristics among opioid overdose decedents in New York City as the epidemic of prescription opioid overdose emerged (largely among Caucasians).

9) National trends in pharmaceutical opioid related overdose deaths compared to other substance related overdose deaths: 1999-2009.

Calcaterra S, Glanz J, Binswanger IA.

Drug Alcohol Depend. 2013 Jan 4. doi:pii: S0376-8716(12)00459-0. 10.1016/j.drugalcdep.2012.11.018. [Epub ahead of print]

Comments: Nice analysis of WONDER data on opioid overdose death, comparing heroin to prescription opioids. As we know, the current epidemic is opioid analgesics, although there has been a more recent increase in heroin deaths – likely due to the transition that often occurs from opioid analgesics to heroin.

10) Patterns of prescription drug misuse among young injection drug users.

Lankenau SE, Teti M, Silva K, Bloom JJ, Harocopos A, Treese M.

J Urban Health. 2012 Dec;89(6):1004-16. doi: 10.1007/s11524-012-9691-9.

Comments: Interesting qualitative analysis of prescription opioid use among young injectors.

11) Transdermal fentanyl in deliberate overdose in pediatrics.

Lyttle MD, Verma S, Isaac R.

Pediatr Emerg Care. 2012 May;28(5):463-4.

Comment: A suicide attempt by multiple fentanyl patches, successfully treated with naloxone infusion and inpatient psychiatric care.

12) Adverse effects associated with non-opioid and opioid treatment in patients with chronic pain.

Labianca R, Sarzi-Puttini P, Zuccaro SM, Cherubino P, Vellucci R, Fornasari D.

Clin Drug Investig. 2012 Feb 22;32 Suppl 1:53-63.

Comment: A review of side effects of multiple different pharmacotherapies for pain.

13) A Review of Potential Adverse Effects of Long-Term Opioid Therapy: A Practitioner’s Guide.

Baldini A, Von Korff M, Lin EH.

Prim Care Companion CNS Disord. 2012;14(3).

Comment: I particularly appreciate the authors’ effort to put some numbers behind opioid analgesic overdose. Based on two prior papers, they state that the rate of overdose among high-dose opioid analgesic users is 1.8% and that 12% of overdoses are fatal, suggesting a death rate of 2 per 1,000 person years of high-dose opioid prescription. I would love to see other analyses with consistent results, but this is certainly a place to start. To put this in context, among heroin users, around 20% overdose in a given year and around 5% of overdoses are fatal.

14) Vital signs: risk for overdose from methadone used for pain relief – United States, 1999-2010.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2012 Jul 6;61(26):493-7.

Comment: Methadone was responsible for about a third of opioid analgesic deaths in 2010. It is important to note that these deaths are mostly from pain prescriptions rather than maintenance programs. In addition, it is important to consider that the causal agents in opioid analgesic deaths vary by state, along with prescribing patterns. For example, this analysis of 13 states did not include Florida, which had an enormous problem with oxycodone/OxyContin prescribing. In fact, a major driver in the transition to methadone for many state insurance programs was the growing OxyContin overdose death epidemic. Nonetheless, there are complexities to titrating methadone that are poorly understood by many providers and most patients

15) A history of being prescribed controlled substances and risk of drug overdose death.

Paulozzi LJ, Kilbourne EM, Shah NG, Nolte KB, Desai HA, Landen MG, Harvey W, Loring LD.

Pain Med. 2012 Jan;13(1):87-95. doi: 10.1111/j.1526-4637.2011.01260.x. Epub 2011 Oct 25.

Comment: Very challenging and intriguing case-control study (300 cases) of prescription overdose death from the CDC injury center. This is a boost in our understanding of the risk factors for overdose death, which include dose of opioids (a surprisingly steep increase in risk with relatively low doses of opioids [as low as 20 morphine equivalents daily]) and number of prescriptions (overlapping prescriptions for opioids appeared to be a major issue). The finding that selected opioids were associated with death is intriguing and worthy of further exploration. The strong association with buprenorphine prescription (although with a very wide confidence interval) is discussed by the authors with a reasonable conclusion that this may be related to resumption of heroin use rather than overdose on buprenorphine itself. The fact that the association with methadone is similar to that with fentanyl and hydromorphone (Dilaudid) suggests that overdose risk may reflect as much the population receiving the prescription as the pharmacology of a given agent.

16) Factors associated with mortality among heroin users after seeking treatment with methadone: A population-based cohort study in Taiwan.

Huang CL, Chung-Wei L.

J Subst Abuse Treat. 2012 Sep 25. pii: S0740-5472(12)00138-9. doi: 10.1016/j.jsat.2012.08.003. [Epub ahead of print]

Comment: Methadone is protective from death, but there still is quite a bit of mortality, including overdose.

17) Factors associated with high-frequency illicit methadone use among rural Appalachian drug users.

1) ‘I saved a life’: a heroin addict’s reflections on managing an overdose using ‘take home naloxone’.

George S, Boulay S, Begley D.

BMJ Case Rep. 2010 Sep 7;2010. doi:pii: bcr0520102986.

Comment: A rare example in the medical literature, this paper includes several paragraphs of direct patient perspective on administering naloxone. Read the free full-text from BMJ.

2) Police Officers’ and Paramedics’ Experiences with Overdose and Their Knowledge and Opinions of Washington State’s Drug Overdose-Naloxone-Good Samaritan Law.

Banta-Green CJ, Beletsky L, Schoeppe JA, Coffin PO, Kuszler PC.

J Urban Health. 2013 Jul 31. [Epub ahead of print]

Comment: Expands on the limited data we have regarding police and paramedics knowledge and opinions regarding opioid overdose prevention initiatives.

3) Development and implementation of an opioid overdose prevention and response program in Toronto, Ontario.

Leece PN, Hopkins S, Marshall C, Orkin A, Gassanov MA, Shahin RM.

Can J Public Health. 2013 Apr 18;104(3):e200-4.

Comment: Unable to access. There have been several papers describing the initial experience of naloxone programs and this is a welcome addition to that literature.

4) Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal in Russian cities.

Coffin PO, Sullivan SD.

J Med Econ. 2013 Jun 19. [Epub ahead of print]

Comments: An adaptation of the model developed for the United States, taking into account structural differences, epidemiologic data, and costs in Russia. Because of limitations in emergency medical services in Russia, the high rate at which overdoses are witnessed, and the very low costs of naloxone, this intervention is likely to be even more cost-effective in Russia than it appears to be in the United States.

5) Use of Naloxone for Clonidine Intoxication in the Pediatric Age Group: Case Report and Review of the Literature.

Ahmad SA, Scolnik D, Snehal V, Glatstein M.

Am J Ther. 2013 Jun 18. [Epub ahead of print]

Comment: I was curious as to why one would use naloxone in this circumstance – and no surprise it did not work.

6) Brief overdose education can significantly increase accurate recognition of opioid overdose among heroin users.

Jones JD, Roux P, Stancliff S, Matthews W, Comer SD.

Int J Drug Policy. 2013 Jun 14. doi:pii: S0955-3959(13)00080-7.

Comment: Brief training on overdose prevention works.

7) Efforts to Reduce Overdose Deaths.

Sherman SG, Han J, Welsh C, Chaulk P, Serio-Chapman C.

Am J Public Health. 2013 Jun 13. [Epub ahead of print]

Schwartz RP, Gryczynski J, O’Grady KE, Sharfstein JM, Warren G, Olsen YK, Mitchell SG, Jaffe JH.

Am J Public Health. 2013 Jun 13. [Epub ahead of print]

Comment: An intriguing dialogue about the Baltimore paper on opioid agonist treatment and overdose. That’s all I’ll say.

8) The feasibility of pharmacy-based naloxone distribution interventions: a qualitative study with injection drug users and pharmacy staff in Rhode Island.

Zaller ND, Yokell MA, Green TC, Gaggin J, Case P.

Subst Use Misuse. 2013 Jun;48(8):590-9. doi: 10.3109/10826084.2013.793355. Epub 2013 Jun 10.

Comment: Unable to access. Interviews with 21 drug injectors and 21 pharmacy staff. Overall there was good acceptance of the concept, although some misinformation about naloxone, some concerns about drug user and pharmacy staff interactions, and some concerns about cost.

9) A Response to the Opioid Overdose Epidemic: Naloxone Nasal Spray.

Wermeling DP.

Drug Deliv Transl Res. 2013 Feb 1;3(1):63-74.

Comments: Unable to access. A review of the rationale for nasal delivery of naloxone.

10) Barriers to medical provider support for prescription naloxone as overdose antidote for lay responders.

Green TC, Bowman SE, Zaller ND, Ray M, Case P, Heimer R.

Subst Use Misuse. 2013 May;48(7):558-67. doi: 10.3109/10826084.2013.787099.

Comments: A qualitative look at providers feelings about providing naloxone to “drug users” and, separately, to “pain patients.” This is a great and useful analysis – and honestly surprisingly positive across the board. The major concern raised seemed to be that naloxone not be the only thing done to try to reduce overdose. This is a pretty dramatic shift in attitudes since earlier evaluations of provider opinion on lay naloxone (Beletsky et al 2007, Coffin et al 2003).

11) Take-Home Emergency Naloxone to Prevent Heroin Overdose Deaths after Prison Release: Rationale and Practicalities for the N-ALIVE Randomized Trial.

Strang J, Bird SM, Parmar MK.

J Urban Health. 2013 May 1. [Epub ahead of print]

Comment: Really interesting article on the design of the N-ALIVE trial of naloxone provision to prisoners pre-release.

12) Changing law from barrier to facilitator of opioid overdose prevention.

Davis C, Webb D, Burris S.

J Law Med Ethics. 2013 Mar;41 Suppl 1:33-6. doi: 10.1111/jlme.12035.

Comments: Excellent analysis of naloxone and Good Samaritan legislation.

13) Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication.

Baumann BM, Patterson RA, Parone DA, Jones MK, Glaspey LJ, Thompson NM, Stauss MP, Haroz R.

Am J Emerg Med. 2013 Mar;31(3):585-8. doi: 10.1016/j.ajem.2012.10.004. Epub 2013 Jan 21.

Comments: Now naloxone can be administered IV, IM, SC, IN, or via nebulizer. I still see limited utility for the nebulizer route, as the medication is used to treat respiratory depression.

14) Early antidote use associated with noninvasive ventilation in prehospital treatment of methadone intoxication.

Gonzva J, Prunet B, Deniel C, Benner P, Toppin F, Brun PM.

Am J Emerg Med. 2013 Feb;31(2):448.e5-6. doi: 10.1016/j.ajem.2012.06.015. Epub 2012 Aug 31. No abstract available.

Comments: This is an intriguing report. Early use of naloxone (by paramedics in this case) may result in less need for intubation, even if patients continue to experience respiratory distress. This suggests that faster administration of pre-hospital naloxone may reduce the need for invasive interventions.

15) Opioid overdose fatality prevention.

Leece P, Orkin A.

JAMA. 2013 Mar 6;309(9):873-4.

Comment: This reply to Beletsky, et al’s, November 2012 commentary Prevention of fatal opioid overdose is followed by the authors’ response.

16) Development of Opioid Overdose Knowledge (OOKS) and Attitudes (OOAS) Scales for take-home naloxone training evaluation.

Williams AV, Strang J, Marsden J.

Drug Alcohol Depend. 2013 Feb 28.

Comment: We are in desperate need of standardized and validated measures for overdose and naloxone distribution. These scales may be useful, although as a word of caution several elements are specific to UK programming.

17) Opioid overdose rates and implementation of overdose education and nasalnaloxone distribution in Massachusetts: interrupted time series analysis.

Walley AY, Xuan Z, Hackman HH, Quinn E, Doe-Simkins M, Sorensen-Alawad A, Ruiz S, Ozonoff A.

BMJ. 2013 Jan 30;346:f174. doi: 10.1136/bmj.f174.

Comments: A long-awaited paper for which the authors deserve high praise, as they have produced the first real evidence of naloxone effectiveness and arguably the most important contribution to naloxone literature to-date. Although not randomized, the interrupted time series analysis is respectable and the results are impressive.

18) Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal.

Coffin PO, Sullivan SD.

Ann Intern Med. 2013 Jan 1;158(1):1-9. doi: 10.7326/0003-4819-158-1-201301010-00003.

Comments: I’ve wanted to write this paper for about a decade, when I thought about cost-effectiveness as three to four calculations on the back of a napkin, rather than years of work and RAM-straining matrices. There’s a long way to go with overdose research that will certainly contribute to future iterations of the model. In the meantime, this is probably a fair, if quite conservative, initial estimate. There is one sensitivity analysis – in which naloxone results in behavior change such that overdose risk is lower – which I suspect may be closer to the actual truth.

19) Naloxone for heroin overdose reversal.

Ann Intern Med. 2013 Jan 1;158(1):I-30. doi: 10.7326/0003-4819-158-1-201301010-00001. No abstract available.

Comments: An excellent editorial from our colleagues at NIDA and the FDA.

20) Prevention of fatal opioid overdose.

Beletsky L, Rich JD, Walley AY.

JAMA. 2012 Nov 14;308(18):1863-4. doi: 10.1001/jama.2012.14205.

Comment: An excellent summary of key issues in overdose prevention and increasing naloxone availability for lay overdose reversal. Read it.

21) Opioid overdose prevention with intranasal naloxone among people who take methadone.

Walley AY, Doe-Simkins M, Quinn E, Pierce C, Xuan Z, Ozonoff A.

J Subst Abuse Treat. 2012 Sep 11. pii: S0740-5472(12)00121-3. doi: 10.1016/j.jsat.2012.07.004. [Epub ahead of print]

Comment: A descriptive piece on the application of the Massachusetts overdose education and naloxone distribution project to methadone maintenance programs. Massachusetts has been a leader in broad-based naloxone distribution and innovative efforts to evaluate the intervention.

22) Prehospital medication administration: a randomised study comparing intranasal and intravenous routes.

McDermott C, Collins NC.

Emerg Med Int. 2012;2012:476161. Epub 2012 Aug 16.

Comment: Naloxone administration by the intranasal route has been increasingly adopted by emergency medical service programs, at least around the United States. However, this route of administration has never been approved by the Food and Drug Administration (this is not unusual or illegal – medical providers frequently use medications “off-label” for indications or by routes that have not gone through the expensive process of FDA approval). This is a nice evaluation of how quickly a drug can be administered by intranasal (87 seconds) compared to IV (178 seconds) and the perceived safety of those two routes of administration. Advanced paramedic trainees preferred the intranasal route.

1) Sublingual Buprenorphine for Chronic Pain: A Survey of Clinician Prescribing Practices.

Rosen K, Gutierrez A, Haller D, Potter JS.

Clin J Pain. 2013 May 30. [Epub ahead of print]

Comments: The use of buprenorphine for chronic pain is an exciting idea whose time has come.

2) Acute Pain Control Challenges with Buprenorphine/Naloxone Therapy in a Patient with Compartment Syndrome Secondary to McArdle’s Disease: A Case Report and Review.

McCormick Z, Chu SK, Chang-Chien GC, Joseph P.

Pain Med. 2013 May 3. doi: 10.1111/pme.12135. [Epub ahead of print]

Comments: Less an overdose article per se, but a paper that pays attention to the overdose issue when titrating opioids.

3)  Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice.

Alhaddad H, Cisternino S, Saubamea B, Schlatter J, Chiadmi F, Risède P, Smirnova M, Cochois-Guégan V, Tournier N, Baud FJ, Mégarbane B.

Toxicology. 2013 Mar 8;305:99-108. doi: 10.1016/j.tox.2013.01.013. Epub 2013 Jan 29.

Comments: An analysis of mechanisms for buprenorphine-induced respiratory depression by mouse gender and strain.

4) Methadone toxicity and possible induction and enhanced elimination in a premature neonate.

George M, Kitzmiller JP, Ewald MB, O’Donell KA, Becter ML, Salhanick S.

J Med Toxicol. 2012 Dec;8(4):432-5. doi: 10.1007/s13181-012-0249-8.

Comments: Methadone pharmaco-kinetics/dynamics are really complicated.

5) Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore, Maryland, 1995-2009.

Schwartz RP, Gryczynski J, O’Grady KE, Sharfstein JM, Warren G, Olsen Y, Mitchell SG, Jaffe JH.

Am J Public Health. 2013 Mar 14. [Epub ahead of print]

Comment: This analysis failed to consider heroin overdose prevention programming – i.e. naloxone distribution – that was scaled up over the exact same period that buprenorphine treatment expanded and heroin overdoses declined. While not all variables can be considered in the interrupted time series approach, not considering the impact of a naloxone-based “overdose prevention program” seems to be a major flaw in the presentation. Disappointing that this was not rigorously addressed.

6) Methadone-related deaths in Montpellier and Region, from 2000 to 2010.

Eiden C, Cathala P, Mathieu-Daude JC, Marson B, Baccino E, Leglise Y, Peyrière H.

Therapie. 2012 Nov-Dec;67(6):515-22.

Comments: Forensic toxicology of methadone deaths.

7) Buprenorphine prescribing practices and exposures reported to a poison center – utah, 2002-2011.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2012 Dec 14;61:997-1001.

Comments:

8) Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice.

Alhaddad H, Cisternino S, Saubamea B, Schlatter J, Chiadmi F, Risède P, Smirnova M, Cochois-Guégan V, Tournier N, Baud FJ, Mégarbane B.

Toxicology. 2013 Jan 29. doi:pii: S0300-483X(13)00018-8. 10.1016/j.tox.2013.01.013. [Epub ahead of print]

Comments: An effort to identify biologic mechanisms for gender variability to buprenorphine respiratory depression.

1) The epidemiology and management of adult poisonings admitted to the short-stay ward of a large Scottish emergency department.

Teo A, Cooper J.

Scott Med J. 2013 Aug;58(3):149-53. doi: 10.1177/0036933013496951.

Comment: I’m unable to access this paper. It’s a review of overdose events at a Scottish hospital; 4% were administered naloxone.

2) EMS Runs for Suspected Opioid Overdose: Implications for Surveillance and Prevention.

Knowlton A, Weir BW, Hazzard F, Olsen Y, McWilliams J, Fields J, Gaasch W.

Prehosp Emerg Care. 2013 Jul-Sep;17(3):317-29. doi: 10.3109/10903127.2013.792888.

Comments: Unable to access, so I’m unclear on details from this paper.

3) Illicit drug overdose – Prevalence and acute management.

Li W, Gunja N.

Aust Fam Physician. 2013 Jul;42(7):481-5.

Comment: Unable to access.  Appears to be a general review of managing illicit drug toxicities.

1) Reducing the health consequences of opioid addiction in primary care.

Bowman S, Eiserman J, Beletsky L, Stancliff S, Bruce RD.

Am J Med. 2013 Jul;126(7):565-71. doi: 10.1016/j.amjmed.2012.11.031. Epub 2013 May 8. Review.

Comment: Kudos to the authors for getting out to primary care providers information on simple harm reduction practices that can be employed in clinical settings.

2) Should North America’s first and only supervised injection facility (InSite) be expanded in British Columbia, Canada?

Jozaghi E, Andresen MM.

Harm Reduct J. 2013 Feb 16;10:1. doi: 10.1186/1477-7517-10-1.

Comment: A discussion including the benefits of supervised injection facilities in reducing overdose deaths, sharing of injection equipment, public drug use, and utilization of emergency medical services.

3) Clinical safety of 1500 mg oral naltrexone overdose.

Reece AS.

BMJ Case Rep. 2010 Sep 7;2010. doi:pii: bcr0420102871. 10.1136/bcr.04.2010.2871. Review.

Comment: The hepatotoxicity concerns with naltrexone were based on doses of around 2 grams, which would be considered massive today.

4) Reducing the Health Consequences of Opioid Addiction in Primary Care.

Bowman S, Eiserman J, Beletsky L, Stancliff S, Bruce RD.

Am J Med. 2013 May 8. doi:pii: S0002-9343(13)00138-1. 10.1016/j.amjmed.2012.11.031. [Epub ahead of print]

Comments: Congratulations to this team on producing what I think are the first primary care guidelines in the scientific literature recommending overdose prevention and naloxone for at-risk patients.

5) ‘It’s more about the heroin’: injection drug users’ response to an overdose warning campaign in a Canadian setting.

Kerr T, Small W, Hyshka E, Maher L, Shannon K.

Addiction. 2013 Mar 28. doi: 10.1111/add.12151. [Epub ahead of print]

Comment: Interesting qualitative analysis of warnings issued regarding high-potency heroin. Respondents instead sought out the suspect drug.

6) Management of opioid analgesic overdose.

Picetti E, Rossi I, Caspani ML.

N Engl J Med. 2012 Oct 4;367(14):1371-3

Comment: Multiple letters in response to the recent review article.

7) Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence.

Krupitsky E, Zvartau E, Blokhina E, Verbitskaya E, Wahlgren V, Tsoy-Podosenin M, Bushara N, Burakov A, Masalov D, Romanova T, Tyurina A, Palatkin V, Slavina T, Pecoraro A, Woody GE.

Arch Gen Psychiatry. 2012 Sep;69(9):973-81.

Comment: This was a randomized, placebo-controlled trial comparing naltrexone implant to oral naltrexone to nothing for preventing relapse to opioid dependence among detoxified patients in Russia. Participants were followed for six months and then followed up a year later to see if there was more death from overdose. The implant was more effective in retaining participants through the six months although by 3 months off therapy there was no difference between the groups. Authors only report “no evidence of increased risk of death due to overdose after  naltrexone treatment” and cite the initial paper showing injectable naltrexone as effective for opioid dependence in Russia (I’m unclear as to why this citation was present). I find this radically insufficient. Naltrexone has lab evidence (animal evidence shows that exposing opioid receptors to naltrexone makes them more sensitive to opioids than mere abstinence) and clinical evidence (high death rates after oral naltrexone treatment) suggesting that it increases risk of overdose and overdose death. The authors of this paper provide no details as to how they showed no evidence of increased overdose. How many people were they able to follow-up with at 18 months (their numbers were really small to begin with)? Did they inquire as to non-fatal overdose? How did they collect information about overdose death (coroners in Russia rarely identify overdose as a cause of death due to stigma and payment issues)? While extended-release naltrexone formulations *might* have less of an association with overdose, the concerns about oral naltrexone are well-established – how did the investigators get approval for oral naltrexone for opioid users from a U.S. government funded study? This is a vulnerable population for whom greater attention to toxicities should be demanded. A high level of attention to overdose outcomes might put to rest these concerns, but I have not seen that as of yet.

8) Staff concerns in heroin-assisted treatment centres.

Demaret I, Lemaître A, Ansseau M.

J Psychiatr Ment Health Nurs. 2012 Aug;19(6):563-7.

Comment: Avoiding overdose is a significant concern for staff at heroin treatment programs. As those who had used benzodiazepines or cocaine have been more likely to overdose in the program, nurses have managed this concern in part by assessing the level of intoxication prior to providing heroin.

9) [Opiates, harm reduction and polysubstance abuse.]

Touzeau D, Courty P.

Presse Med. 2012 Oct 31. doi:pii: S0755-4982(12)00524-6. 10.1016/j.lpm.2012.07.038. [Epub ahead of print] French.

Comment: A review of opioids and harm reduction in French, which I cannot read.