PubMed Update August 2016

A robust 20 papers this month. There are some excellent manuscripts this month, including several on fentanyl. I want to draw particular attention to a few papers that will be important reads for some of you: #1 addresses concurrent use of methamphetamine with heroin, #12 explores different “types” of opioid overdose, #17 reviews the foundational papers upon which much overdose research/knowledge today is based, and #19 compares deaths due to heroin to those due to prescription opioids.

1) Prevalence and Correlates of Heroin-Methamphetamine Co-Injection Among Persons Who Inject Drugs in San Diego, California, and Tijuana, Baja California, Mexico.

Meacham MC, Strathdee SA, Rangel G, Armenta RF, Gaines TL, Garfein RS.

J Stud Alcohol Drugs. 2016 Sep;77(5):774-81.

Comments: Really interesting results with regard to methamphetamine – co-use of methamphetamine increased overdose risk in San Diego but not Tijuana, suggesting that risk may have been behavioral rather than pharmacologic.

2) Combating Opioid Overdose With Public Access to Naloxone.

Mitchell KD, Higgins LJ.

J Addict Nurs. 2016 Jul-Sep;27(3):160-79. doi: 10.1097/JAN.0000000000000132.

Comments: Review of naloxone literature with an eye toward how it influences nursing.

3) Prescription opioids prior to injection drug use: Comparisons and public health implications.

Al-Tayyib AA, Koester S, Riggs P.

Addict Behav. 2016 Aug 19. pii: S0306-4603(16)30296-9. doi: 10.1016/j.addbeh.2016.08.016. [Epub ahead of print]

Comments: Those who initiated injection with prescription opioids were higher risk than those who started with heroin in the Denver Colorado’s NHBS cohort.

4) Awareness and Attitudes Toward Intranasal Naloxone Rescue for Opioid Overdose Prevention.

Kirane H, Ketteringham M, Bereket S, Dima R, Basta A, Mendoza S, Hansen H.

J Subst Abuse Treat. 2016 Oct;69:44-9. doi: 10.1016/j.jsat.2016.07.005. Epub 2016 Jul 18.

Comments: Investigators asked patients and providers how they thought things *would* change if they gave/received naloxone kits and found quite a few thought use would increase. In contrast, looking at what “did” happen suggests the opposite (see next month’s PubMed Update).

PubMed Update May 2016

19 this month. Enjoy!

1) Methadone-Related Overdose Deaths in a Liberal Opioid Maintenance Treatment Programme.

Tjagvad C, Skurtveit S, Linnet K, Andersen LV, Christoffersen DJ, Clausen T.

Eur Addict Res. 2016 Jun 1;22(5):249-258. [Epub ahead of print]

Comments: Patients on very high doses of methadone or also using benzodiazepines were at higher risk of death.

2) Heroin use.

Salani DA, Zdanowicz M, Joseph L.

J Psychosoc Nurs Ment Health Serv. 2016 Jun 1;54(6):30-7. doi: 10.3928/02793695-20160518-05.

Comments: Epidemiologic review.

3) Academic physicians' and medical students' perceived barriers toward bystander administered naloxone as an overdose prevention strategy.

Gatewood AK, Van Wert MJ, Andrada AP, Surkan PJ.

Addict Behav. 2016 May 17;61:40-46. doi: 10.1016/j.addbeh.2016.05.013. [Epub ahead of print]

Comments: Qualitative interviews with medical providers.

4) Patient Characteristics and Outcomes in Unintentional, Non-fatal Prescription Opioid Overdoses: A Systematic Review.

Elzey MJ, Barden SM, Edwards ES.

Pain Physician. 2016 May;19(4):215-28.

Comments: Non-fatal events are far more common, not well-predicted by risk factors, and in need of additional research.

5) Incorporation of poison center services in a state-wide overdose education and naloxone distribution program.

Doyon S, Benton C, Anderson BA, Baier M, Haas E, Hadley L, Maehr J, Rebbert-Franklin K, Olsen Y, Welsh C.

Am J Addict. 2016 Jun;25(4):301-6. doi: 10.1111/ajad.12384. Epub 2016 May 24.

Comments: Interesting case series of naloxone reversals reported to poison control. They report a 75.6% “response rate” although some of the remainder was “unknown” and was there were only 2 deaths among 78 cases, suggesting a rate closer to 97.5%. Response rate to heroin was higher than for prescription opioids. Of the 43 suspected heroin events, 31 went to the ED, 25 were discharged, and 5 required ICU care. Of 31 suspected prescription opioid 20 went to the ED, 9 were discharged, and 6 required ICU care. This is consistent with the more complicated nature of prescription opioid overdose.

6) Police Officers Can Safely and Effectively Administer Intranasal Naloxone.

Fisher R, O'Donnell D, Ray B, Rusyniak D.

Prehosp Emerg Care. 2016 May 24:1-6. [Epub ahead of print]

Comments: About a 65% response rate among 117 administrations and 1 combative individual.

PubMed Update April 2016

23 for this month! Lots of interesting stuff, from large-scale epidemiology to randomized controlled trials.

1) Pharmacokinetic Properties and Human Use Characteristics of an FDA Approved IntranasalNaloxone Product for the Treatment of Opioid Overdose.

Krieter P, Chiang N, Gyaw S, Skolnick P, Crystal R, Keegan F, Aker J, Beck M, Harris J.

J Clin Pharmacol. 2016 May 5. doi: 10.1002/jcph.759. [Epub ahead of print]

Comment: Details on the pharmacokinetics and usability studies for the new nasal device.

2) The use of public health infrastructure probably the best strategy for national and large-scalenaloxone distribution programmes.

Madah-Amiri D, Clausen T.

Addiction. 2016 May 3. doi: 10.1111/add.13400. [Epub ahead of print] No abstract available.

Comment: Large-scale naloxone requires public health support.

3) The Opioid Epidemic in the United States.

Wilkerson RG, Kim HK, Windsor TA, Mareiniss DP.

Emerg Med Clin North Am. 2016 May;34(2):e1-e23. doi: 10.1016/j.emc.2015.11.002. Epub 2016 Feb 17. Review.

Comment: Focuses on risk factors for problematic opioid use and naloxone.

PubMed Update January 2014

10 papers this month, half of which relate to the United Kingdom. We continue to move forward.

1) Characterization of opioid overdose and response in a high-risk community corrections sample: A preliminary study.

Cropsey KL, Martin S, Clark CB, McCullumsmith CB, Lane PS, Hardy S, Hendricks PS, Redmond N.

J Opioid Manag. 2013 Nov-Dec;9(6):393-400.

Comments: Valuable survey of persons in the corrections system, under community supervision. Nearly half had used opioids and 40% of those had experienced an opioid overdose. Those who had overdosed were more likely to be white, female, and have higher educational attainment; they were also much more likely to have witnessed overdose, have seen someone die of overdose, and want training in overdose prevention and management.

2) Opioids Compared to Placebo or Other Treatments for Chronic Low Back Pain: An Update of the Cochrane Review.

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

Spine (Phila Pa 1976). 2014 Jan 29. [Epub ahead of print]

Comments: A review of studies evaluating short term use of opioids for chronic lower back pain. The studies evaluated all have major shortcomings so we’re left with little new information.

3) Opioid overdose with gluteal compartment syndrome and acute peripheral neuropathy.

Adrish M, Duncalf R, Diaz-Fuentes G, Venkatram S.

Am J Case Rep. 2014 Jan 15;15:22-6

Comments: Being “down” with an overdose for a prolonged period can lead to complications such as rhabdomyolysis and nerve compression. This patient developed compartment syndrome, which is to say high pressure within the fascial compartment of the buttocks, requiring surgical intervention to spare her extremity.

PubMed Update November/December 2013

We close out 2013 with an impressive 25 papers in the final two months for a total count of 89 papers. Some interesting new approaches and perspectives, including a paper on the underappreciated role of adulterants, a couple of naltrexone papers, and lots of lay naloxone.

1) The Whole Is Just the Sum of Its Parts: Limited Polydrug Use Among the "Big Three" Expensive Drugs in the United States.

Caulkins JP, Everingham S, Kilmer B, Midgette G.

Curr Drug Abuse Rev. 2013 Dec 5. [Epub ahead of print]

Comments: Somewhat surprising data suggesting relatively separate markets for heroin, cocaine and methamphetamine.

2) A systematic review and meta-analysis of naltrexone implants for the treatment of opioid dependence.

Larney S, Gowing L, Mattick RP, Farrell M, Hall W, Degenhardt L.

Drug Alcohol Rev. 2013 Dec 3. doi: 10.1111/dar.12095. [Epub ahead of print]

Comments: A systematic review concluding that the data for naltrexone implants for opioid dependence are insufficient for use outside of clinical trials.

3) Trends and Regional Variation in Opioid Overdose Mortality Among Veterans Health Administration Patients, Fiscal Year 2001 to 2009.

Bohnert AS, Ilgen MA, Trafton JA, Kerns RD, Eisenberg A, Ganoczy D, Blow FC.

Clin J Pain. 2013 Nov 25. [Epub ahead of print]

Comments: What happened with opioid analgesic overdose deaths in the United States also happened in among veterans receiving care in the Veterans’ Administration.

4) The Dueling Obligations of Opioid Stewardship.

Coffin P, Banta-Green C.

Ann Intern Med. 2013 Dec 10. doi: 10.7326/M13-2781. [Epub ahead of print] No abstract available.

Comments: Commentary on the reliance on opioids and minimizing the potential harms of stewardship efforts.

PubMed Update September 2013

12 articles this month.

1) Effectiveness of Naltrexone in the Prevention of Delayed Respiratory Arrest in Opioid-Naive Methadone-Intoxicated Patients.

Aghabiklooei A, Hassanian-Moghaddam H, Zamani N, Shadnia S, Mashayekhian M, Rahimi M, Nasouhi S, Ghoochani A.

Biomed Res Int. 2013;2013:903172. Epub 2013 Sep 9.

Comments: Interesting use of the long-acting opioid antagonist naltrexone in this study from Iran. The likely downside of this approach of course is that, in those with opioid dependence (constituting the vast majority of overdose cases), it doesn’t allow for titration of antagonist effect to minimize withdrawal symptoms.

2) An investigation of the interactions between methadone and elvitegravir/cobicistat in subjects receiving chronic methadone maintenance.

Bruce RD, Winkle P, Custodio JM, Wei X, Rhee MS, Kearney BP, Ramanathan S, Friedland GH.

Antimicrob Agents Chemother.2013 Sep 30. [Epub ahead of print]

Comments: This is a promising finding for the new HIV regimen.

3) Interaction of Different Antidepressants with Acute and Chronic Methadone in Mice, and Possible Clinical Implications.

Schreiber S, Barak Y, Hostovsky A, Baratz-Goldstein R, Volis I, Rubovitch V, Pick CG.

J MolNeurosci.2013 Sep 22. [Epub ahead of print]

Comments: Really interesting study, since many opioid overdoses occur in the presence of anti-depressant medications. These results are too preliminary to draw strong conclusions, but it’s an important pursuit.

4) Law enforcement attitudes toward overdose prevention and response.

Green TC, Zaller N, Palacios WR, Bowman SE, Ray M, Heimer R, Case P.

Drug Alcohol Depend.2013 Sep 2.doi:pii: S0376-8716(13)00334-7. 10.1016/j.drugalcdep.2013.08.018. [Epub ahead of print]

Comments: Interesting qualitative analysis of police attitudes toward lay naloxone.

5) Days of heroin use predict poor self-reported health in hospitalized heroin users.

Meshesha LZ, Tsui JI, Liebschutz JM, Crooks D, Anderson BJ, Herman DS, Stein MD.

Addict Behav. 2013 Aug 14;38(12):2884-2887. doi:

Comments: More days of heroin use is associated with worse self-reported health and worse self-reported health is associated with non-fatal overdose events.

6) Assisted injection among people who inject drugs in Thailand.

Lee WK, Ti L, Hayashi K, Kaplan K, Suwannawong P, Wood E, Kerr T.

Subst Abuse Treat Prev Policy. 2013 Sep 10;8(1):32. [Epub ahead of print]

Comments: This is a useful contribution to overdose literature. There has long been a concern that people who require assistance to inject (often women) would overdose more. This hasn’t held up in studies and this study corroborates that lack of association. It may be well worth exploring further, but thus far we don’t have any evidence that assistance with injecting increases overdose risk.

7) BET 3: Is nebulised naloxone effective in opioid overdose?

[No authors listed]

Emerg Med J. 2013 Oct;30(10):860. doi: 10.1136/emermed-2013-203100.3.

Comments: Yes, in breathing patients.

8) The lethal burden of drug overdose.

[No authors listed]

Lancet. 2013 Sep 7;382(9895):833. doi: 10.1016/S0140-6736(13)61844-9. No abstract available.

Comments: Brief commentary on opioid overdose mortality in UK and US. Notable that there is no mention of naloxone.

9) [Maintaining opioid abstinence long after inpatient treatment with opioid substitution in an addictology hospital unit].

Bouab O, Lahmek P, Meunier N, Aubin HJ, Michel L.

Rev Med Brux. 2013 May-Jun;34(3):132-40. French.

Comments: Basically inpatient withdrawal from agonist maintenance treatment.

10) The pharmacokinetic and pharmacodynamic interactions between buprenorphine/naloxone and elvitegravir/cobicistat in subjects receiving chronic buprenorphine/naloxone treatment.

Bruce RD, Winkle P, Custodio JM, Wei LX, Rhee MS, Kearney BP, Ramanathan S, Friedland GH.

J Acquir Immune DeficSyndr. 2013 Aug 1;63(4):480-4. doi: 10.1097/QAI.0b013e3182961d31.

Comments: The new combined HIV med (Stribild) modestly increases buprenorphine levels.

11) Problem based review: The patient taking methadone.

Arora A, Williams K.

Acute Med. 2013;12(1):51-4. Review.

Comments: Methadone maintenance review.

12) Low-frequency heroin injection among out-of-treatment, street-recruited injection drug users.

Harris JL, Lorvick J, Wenger L, Wilkins T, Iguchi MY, Bourgois P, Kral AH.

J Urban Health. 2013 Apr;90(2):299-306. doi: 10.1007/s11524-012-9720-8.

Comments: Another useful contribution – infrequent heroin injectors had a lower risk of non-fatal overdose. As with most overdose epidemiology, the relationship between use frequency and overdose risk is likely complex.

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 August 2013

16 papers today – this is getting to be a big job. Naloxone, fentanyl, methadone, stars, pain, Central Asia, primary care, injection facilities, personal stories …

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) 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.

3) 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.

4) 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.

PubMed Update October/November 2012

My apologies for tardiness. I'll try to be on time next month. 13 papers described below.

1. 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.

2. 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.

3. 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.

Pubmed April 2012 Update

Here we go with April 2012 ...

Mortality and causes of death among users of methadone maintenance treatment in Israel, 1999-2008.

Rosca P, Haklai Z, Goldberger N, Zohar P, Margolis A, Ponizovsky AM.

Drug Alcohol Depend. 2012 Apr 6. [Epub ahead of print]

Comment: Rate of overdose mortality was 0.22/100 person-years (i.e. 0.22%), one-quarter to one-fifth the expected rate in most studies of other cohorts

Intravenous use of illicit buprenorphine/naloxone to reverse an acute heroin overdose.

Yokell MA, Zaller ND, Green TC, McKenzie M, Rich JD.

J Opioid Manag. 2012 Jan-Feb;8(1):63-6.

Comment: Buprenorphine is a partial agonist with a ceiling effect that limits the capacity for overdose among those with a tolerance to opioids. Like naloxone, buprenorphine really likes binding to opioid receptors and kicks most other opioids out. Since buprenorphine out-competes other opioids for receptors and has a ceiling effect, administration in the setting of overdose may result in reversal of opioid overdose. That said, this wouldn't be the approach I would advocate for dissemination since (1) buprenorphine could cause overdose in an opioid user with minimal tolerance and (2) buprenorphine could cause prolonged withdrawal (for over a day) in those with a very high tolerance.

Understanding drug-related mortality in released prisoners: A review of national coronial records.

Andrews JY, Kinner SA.

BMC Public Health. 2012 Apr 4;12(1):270. [Epub ahead of print]

Comment: An interesting exploration of circumstances surrounding prisoner death post-release.

Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide.

Goli V, Webster LR, Lamson MJ, Cleveland JM, Sommerville KW, Carter E.

Harm Reduct J. 2012 Mar 15;9(1):13. [Epub ahead of print]

Comment: An intriguing analysis of whether or not injecting the pre-formulated morphine + naltrexone actually blocks the effects of morphine. It appears to partially, but not completely, block the effect.

Incidence and risk factors for non-fatal overdose among a cohort of recently incarcerated illicit drug users.

Kinner SA, Milloy MJ, Wood E, Qi J, Zhang R, Kerr T.

Addict Behav. 2012 Feb 7. [Epub ahead of print]

Comment: Prior overdose, daily or binge drug use, and public injecting are associated with nonfatal overdose among recently released drug users.

Dexmedetomidine infusion to facilitate opioid detoxification and withdrawal in a patient with chronic opioid abuse.

Upadhyay SP, Mallick PN, Elmatite WM, Jagia M, Taqi S.

Indian J Palliat Care. 2011 Sep;17(3):251-4.

Comment: An interesting use of a particular sedative to assist with opioid withdrawal in an intensive care unit.

Drug-related deaths with evidence of intracorporeal drug concealment at autopsy: five case reports.

Wilcher G.

Am J Forensic Med Pathol. 2011 Dec;32(4):314-8.

Comment: Intriguing review of 5 cases of drug-induced death among "body packers" or "body stuffers", including a review of that language. Interestingly, most of the deaths were due to overdose on consumed drugs rather than toxicity from rupture of drug packets.