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. 

PubMed Update May 2013

Here is the May 2013 roundup with 7 papers and some extra kudos to the authors for important steps forward in data or practice.

1) 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?

2) 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.

3) 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.

4) 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.

5) 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.

6) 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.

7) 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).

PubMed Update February/March 2013

Another 8 papers on opioid overdose issues.

1) '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.

2) 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.

3) 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).

4) 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.

5) 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.

News: FDA denies Reckitt's request to block generic buprenorphine/naloxone tablets

The U.S. Food and Drug Administration has roundly denied all requests from Reckitt-Benckiser to block approval of generic buprenorphine/naloxone tablets. This request was made at the time when the monopoly on the product was ending and was based on risks of pediatric exposures that the company claimed were higher with the tablet than their new film product. The FDA provided an excellent review of the issues and rejected all components of the request.

This is an enormous relief for public health agencies providing buprenorphine services, many of which would have dropped buprenorphine services altogether or would have ceased to provide the buprenorphine/naloxone formulation due to cost.

Scotland's Stephen Malloy talks about why naloxone is important

Press release: Naloxone cost-effective

City and County of San Francisco Edwin M. Lee Mayor

San Francisco Department of Public Health Barbara A. Garcia, MPA Director of Health

Embargoed until 5p.m. Eastern Time	Eileen Shields, Public Information Officer
December 31, 2012	415/554-2507 (o) 415/370-3377 (cell) Eileen.Shields@sfdph.org

Study Shows Naloxone Cost-Effective in Preventing Overdose Deaths

San Francisco, CA, January 1, 2013 - The Annals of Internal Medicine released a study this week demonstrating that giving heroin users the overdose antidote naloxone is a cost-effective way to prevent overdose death and save lives. Phillip Coffin, MD, Director of Substance Use Research at the San Francisco Department of Public Health and Assistant Clinical Professor at the University of California San Francisco, and Sean Sullivan, PhD, Professor and Director of the Pharmaceutical Outcomes Research and Policy Program at the University of Washington, co-authored the study.

Drug overdose is now the leading cause of injury death in the United States with opioids, such as heroin, accounting for about 80% of those deaths. Naloxone is a safe and effective antidote that works by temporarily blocking opioid receptors. As of 2010, 183 public health programs around the country, including those supported by the San Francisco Department of Public Health, had trained over 53,000 individuals in how to use naloxone. These programs had documented more than 10,000 cases of successful overdose reversals.

The authors of this study developed a mathematical model to estimate the impact of distributing naloxone in this way. Their model was based on conservative estimates of the number of overdoses that occur each year. It accounted for people who overdose repeatedly, and it acknowledged that most people who overdose will survive whether or not they get naloxone.

In their basic model, Coffin and Sullivan estimated that reaching 20% of a million heroin users with naloxone would prevent about 9,000 overdose deaths over their lifetime. One life would be saved for every 164 naloxone kits given out. Based on optimistic assumptions, naloxone could prevent as many as 43,000 deaths – one life for every 36 kits given out.

Naloxone distribution would cost about $400 for every quality-adjusted year of life gained. This value is well below the customary $50,000 cutoff for medical interventions. It is also cheaper than most well-accepted prevention programs in medicine – most similar to the cost-effectiveness of smoking cessation or checking blood pressure. All reasonable assumptions produced costs that were well within traditional guidelines for cost-effectiveness.

“Naloxone is a highly cost-effective way to prevent overdose deaths,” said Dr Coffin. “And, as a researcher at the Department of Public Health, my priority is maximizing our resources to help improve the health of the community.”

Naloxone distribution has existed in San Francisco since the late 1990s, with SFDPH support since 2004. During that time, heroin overdose fatalities slowly decreased from a peak of 155 in 1995 to 10 in 2010. Opioid analgesic deaths (e.g., oxycodone, methadone, or hydrocodone) remain elevated, with 121 deaths in 2010. Efforts are currently underway to expand access to this lifesaving medication for patients receiving prescription opioids as well.

Contact Information and Follow-up

To obtain a copy of this study, see Annals of Internal Medicine

To discuss the paper, contact Dr. Coffin, pcoffin@gmail.com

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Scottish naloxone website

Check out the new naloxone website from the Scottish Drugs Forum, a leader in naloxone distribution to drug users: http://naloxone.org.uk/.

Good stuff: the site is easy to navigate and includes training videos, research and materials for overdose programs.

In this video, Stephen Malloy, the national coordinator for take-home naloxone in Scotland, talks about why they created the website. 

Police Training Video

A (really excellent) training video for police regarding Washington State's 911 Good Samaritan and Lay Naloxone law can now be found here.

The 5.5 minute video can be found directly at Seattle Police Department Training Video.

It is narrated by Captain Les Liggins of the Seattle Police Department, Mary Barbosa of the King County Prosecutor's Office, and Dr Charissa Fontinos of Public Health Seattle & King County

Pubmed March 2012 Update

A number of good papers this month! Most notable are the MMWR report and the intriguing Copenhagen data on opioid overdoses attended by emergency medical services.

Buprenorphine vs methadone treatment: A review of evidence in both developed and developing worlds.

Whelan PJ, Remski K.

J Neurosci Rural Pract. 2012 Jan;3(1):45-50.

Comment: Includes a brief review of the lower overdose risk with buprenorphine.

Delayed leukoencephalopathy after alprazolam and methadone overdose: A case report and review of the literature.

Carroll I, Heritier Barras AC, Dirren E, Burkhard PR, Horvath J.

Clin Neurol Neurosurg. 2012 Feb 16. [Epub ahead of print] No abstract available.

Comment: The precipitating event in this case is a hypoxic event in a patient with an enzyme deficiency, not a direct opioid or benzodiazepine toxicity.

Community-based opioid overdose prevention programs providing naloxone - United States, 2010.

Centers for Disease Control and Prevention (CDC).

MMWR Morb Mortal Wkly Rep. 2012 Feb 17;61:101-5.

Comment: Hooray! Read this for a review of U.S. nationwide naloxone program data.

Chromatographic determination of drugs of abuse in vitreous humor using solid-phase extraction.

Fernández P, Seoane S, Vázquez C, Tabernero MJ, Carro AM, Lorenzo RA.

J Appl Toxicol. 2012 Feb 15. doi: 10.1002/jat.2722. [Epub ahead of print]

Comment: An interesting method for identifying several drugs of abuse simoultaneously.

Opioid-dependent error processing.

Fellows-Smith J.

J Opioid Manag. 2011 Nov-Dec;7(6):443-9.

Comment: The importance of this article is not reflected in the title. This is a data linkage study in Australia looking at mortality rates among those receiving methadone (0.7%) versus naltrexone (2.6%) for opioid therapy. Again this raises the major concerns about opioid overdose after naltrexone therapy, concerns that were clearly inadequately addressed prior to FDA approval of naltrexone for opioid dependence.

Attitudes and knowledge about naloxone and overdose prevention among detained drug users in Ningbo, China.

Liu Y, Bartlett N, Li L, Lv X, Zhang Y, Zhou W.

Subst Abuse Treat Prev Policy. 2012 Feb 8;7(1):6. [Epub ahead of print]

Comment: Incarcerated drug users would like to have naloxone.

Comparative analysis of pathological and toxicological features of opiate overdose and non-overdose fatalities.

Soravisut N, Rattanasalee P, Junkuy A, Thampitak S, Sribanditmongkol P.

J Med Assoc Thai. 2011 Dec;94(12):1540-6.

Comment: There's an error in this title - it should be opiate versus non-opiate overdose deaths. Basic epidemiology.

Treatment of opioid overdose in a physician-based prehospital EMS: frequency and long-term prognosis.

Nielsen K, Nielsen SL, Siersma V, Rasmussen LS.

Resuscitation. 2011 Nov;82(11):1410-3. Epub 2011 Jun 15.

Comment: Very useful review of opioid overdoses attended by emergency medical services in Copenhagen. Of 3245 cases, 69% were released at the scene without transport to the hospital, 11% had cardiac arrest at the scene, 21% were admitted to the hospital, and 10% died. These data seem pretty consistent with my current understanding of EMS attended overdoses. Nonetheless, I find these data intensely interesting because, notwithstanding many theories, we still don't really know what happens to the overdoses that occur in the community.

Prehospital treatment of opioid overdose in Copenhagen--is it safe to discharge on-scene?

Rudolph SS, Jehu G, Nielsen SL, Nielsen K, Siersma V, Rasmussen LS.

Resuscitation. 2011 Nov;82(11):1414-8. Epub 2011 Jul 2.

Comment: This is a sub-analysis of the prior study. They looked at the 69% of people that were released after naloxone was given and not transported to the hospital. They found that 3 of 2241 individuals died from a suspected "rebound overdose" after naloxone was given. Put in other words, 0.1% of overdose victims who were given naloxone at the scene and then released fell back into an opioid overdose and died. The authors looked pretty deeply into the circumstances post-release, so I think these data are reliable. While this figure is impressively low, it does reaffirm the need for bystanders to stay with overdose victims for several hours after reversing an overdose.

Potential role of safer injection facilities in reducing HIV and hepatitis C infections and overdose mortality in the United States.

Semaan S, Fleming P, Worrell C, Stolp H, Baack B, Miller M.

Drug Alcohol Depend. 2011 Nov 1;118(2-3):100-10. Epub 2011 Apr 23.

Comment: A review of data on supervised injection facilities, which have impressive data on reducing local overdose mortality in Vancouver.

Methadone, another cause of opioid-associated hearing loss: a case report.

Shaw KA, Babu KM, Hack JB.

J Emerg Med. 2011 Dec;41(6):635-9. Epub 2010 Dec 9.

Comment: An unusual toxicity to opioid overdose, but one that has been previously documented. Generally neurologic in origin and reversible with removal of the offending opioid agent.