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 July 2014

Hooray for a mere 7 paper reprieve this month.

1) Underrepresentation of Heroin Involvement in Unintentional Drug Overdose Deaths in Allegheny County, PA.

Mertz KJ, Janssen JK, Williams KE.

J Forensic Sci. 2014 Jul 16. doi: 10.1111/1556-4029.12541. [Epub ahead of print]

Comments: This manuscript presents critical and very concerning results regarding interpretation of our prescription opioid overdose epidemic. Morphine and codeine are commonly present and without 6-MAM (a third heroin metabolite) present at sufficient levels those deaths are coded as morphine and codeine. On this review of 112 such deaths, 66% met criteria for heroin involvement based on a history of heroin use (which may not be sufficient given the frequent use of other opioids among heroin users), drug paraphernalia or stamp bags, track marks, and detection of 6-MAM (generally at very low levels). Good toxicologists always check for 6-MAM so that shouldn’t be a major issue, but it is conceivable that some of these morphine/codeine cases are in fact heroin – an important caveat as we respond to the epidemic.

2) Legislative strategies other than legalizing illicit opioids may help to reduce overdose fatalities.

Trafton JA, Oliva EM.

Addiction. 2014 Aug;109(8):1243-4. doi: 10.1111/add.12585. No abstract available.

Comments: Authors argue that Good Samaritan and naloxone legislation may be effective strategies to reduce overdose.

3) Prevalence and factors associated with HIV infection among injection drug users at methadone clinics in Taipei, Taiwan.

Yen YF, Yen MY, Lin T, Li LH, Jiang XR, Chou P, Deng CY.

BMC Public Health. 2014 Jul 4;14(1):682. doi: 10.1186/1471-2458-14-682.

Comments: Again, HIV infection is associated with a history of overdose among persons who inject drugs.

4) Methadone toxicity in a poisoning referral center.

Taheri F, Yaraghi A, Sabzghabaee AM, Moudi M, Eizadi-Mood N, Gheshlaghi F, Farajzadegan Z.

J Res Pharm Pract. 2013 Jul;2(3):130-4. doi: 10.4103/2279-042X.122387.

Comments: an analysis of methadone poisonings in Iran. Among 385 patients, 57.7% of cases were “intentional” and demonstrated high rates of psychiatric disorders (25.8%). Among the full cohort, 40% had opioid use disorders and 25.5% were in a methadone program.

PubMed Update May/June 2014

25 papers in two months. Anyone want to help with this?

1) Naloxone therapy in opioid overdose patients: intranasal or intravenous? A randomized clinical trial.

Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, Zandifar S.

Arch Med Sci. 2014 May 12;10(2):309-14. doi: 10.5114/aoms.2014.42584. Epub 2014 May 13.

PMID: 24904666 [PubMed] Free PMC Article

Comments: More data to support the utility of intranasal naloxone for overdose reversal. There are, however, some odd findings that suggest caution in interpreting the paper. The authors used 0.4mg of naloxone for IV or IN administration, whereas most efforts utilize 2mg for IN administration given the lower bioavailability. Moreover, they had a higher level of consciousness in the IN group, which seems odd.

2) Brugada Phenocopy in Concomitant Ethanol and Heroin Overdose.

Rambod M, Elhanafi S, Mukherjee D.

Ann Noninvasive Electrocardiol. 2014 Jun 5. doi: 10.1111/anec.12171. [Epub ahead of print]

PMID: 24903622 [PubMed - as supplied by publisher]

Comments: There are cases in which opioids can result in unstable heart rhythms. Usually this is related to high dose methadone, prolongation of the QT interval and torsades de pointes. In this case, heroin plus alcohol may have resulted in electrical conduction similar to “Brugada syndrome” which, in the interest of having an image in this blog post, I’ve posted an image of here. This type of electrical conduction is usually genetic and can result in sudden death through lethal arrhythmias.

3) A systematic review of community opioid overdose prevention and naloxone distribution programs.

Clark AK, Wilder CM, Winstanley EL.

J Addict Med. 2014 May-Jun;8(3):153-63. doi: 10.1097/ADM.0000000000000034.

PMID: 24874759 [PubMed - in process]

Comments: An impressive review of existing data for naloxone programs. Big kudos to the authors.

4) Intravenous methadone application as a serious risk factor for an overdose death: methadone-related fatalities in Hamburg from 2007 to 2012.

Iwersen-Bergmann S, Jungen H, Andresen-Streichert H, Müller A, Elakkary S, Püschel K, Heinemann A.

Int J Legal Med. 2014 May 25. [Epub ahead of print]

PMID: 24859230 [PubMed - as supplied by publisher]

Comments: Interesting analysis of methadone-related deaths among methadone maintenance patients suggesting that, while overdose deaths are not common, many may have been related to IV use of methadone.

5) Abnormal intracellular calcium homeostasis associated with vulnerability in the nerve cells from heroin-dependent rat.

Liu X, Wang G, Pu H, Jing H.

Brain Res. 2014 Jul 14;1572:40-9. doi: 10.1016/j.brainres.2014.05.016. Epub 2014 May 20.

PMID: 24854119 [PubMed - in process]

Comments: Intriguing analysis of rat brains suggesting a key role of calcium in neurotoxicity related to heroin use. Do medications like verapamil, generally used to manage hypertension, have a role in preventing neurologic damage from opioids and perhaps even reducing overdose risk?

6) Source of prescription drugs used nonmedically in rural and urban populations.

Wang KH, Fiellin DA, Becker WC.

Am J Drug Alcohol Abuse. 2014 Jul;40(4):292-303. doi: 10.3109/00952990.2014.907301. Epub 2014 May 22.

PMID: 24853143 [PubMed - in process]

Comments: Around a fifth of people using prescription opioids “non-medically” get them directly from a physician.

PubMed Update February 2014

8 papers today, essentially about naloxone and heroin.

1) Risk of anaphylaxis in opioid dependent persons: effects of heroin versus substitution substance.

Maurer U, Kager C, Fellinger C, Loader D, Pollesböck A, Spitzer B, Jarisch R.

Subst Abuse Treat Prev Policy. 2014 Feb 27;9(1):12. [Epub ahead of print]

Comment: Seeking alternative explanations for “overdose”, the authors explored histamine levels in heroin using individuals. They found that heroin users had greater spikes in histamine levels when exposed to IV heroin compared to oral morphine. They hypothesized that this may explain why so many cases of overdose have a sublethal concentration of opioids, but this seems an overreach based on their data.

2) Effective use of naloxone among people who inject drugs in Kyrgyzstan and Tajikistan using pharmacy- and community-based distribution approaches.

Kan M, Gall JA, Latypov A, Gray R, Alisheva D, Rakhmatova K, Sadieva AS.

Int J Drug Policy. 2014 Jan 23. pii: S0955-3959(14)00008-5. doi: 10.1016/j.drugpo.2014.01.005. [Epub ahead of print]

Comment: 47 to 81% of naloxone kits given out in Kyrgyzstan and Tajikistan were used to reverse an overdose – remarkable numbers, from 3 to 5 times higher than seen in western states.

3) Norway tries naloxone in spray form to prevent deaths from drug overdose.

Hansen A.

BMJ. 2014 Feb 20;348:g1686. doi: 10.1136/bmj.g1686. No abstract available.

Comment: Naloxone in Norway.

4) Naloxone induces endoplasmic reticulum stress in PC12 cells.

Seo S, Kwon YS, Yu K, Kim SW, Kwon OY, Kang KH, Kwon K.

Mol Med Rep. 2014 Apr;9(4):1395-9. doi: 10.3892/mmr.2014.1935. Epub 2014 Feb 7.

Comment: I can only see the abstract for this one and the science is outside of my realm – I’m unable to identify anything of apparent clinical relevance.

5) Naloxone for Opioid Overdose Prevention: Pharmacists' Role in Community-Based Practice Settings.

Bailey AM, Wermeling DP.

Ann Pharmacother. 2014 Feb 12. [Epub ahead of print]

Comment: Very helpful and relevant summary of some pharmacists experience with dispensing naloxone.

6) A case of heroin induced sensorineural hearing loss.

Aulet RM, Flis D, Sillman J.

Case Rep Otolaryngol. 2014;2014:962759. doi: 10.1155/2014/962759. Epub 2014 Jan 6.

Comment: Another case of opioid overdose-related sensorineural hearing loss, which means hearing loss from the cochlea (inner ear). The authors kindly run through some theories, including hypotension (e.g. reduced blood flow to the inner ear), overstimulation of kappa opioid receptors present in the cochlea, or adulteration with an ototoxic substance such as quinine.

7) Overdose prevention in injecting opioid users: The role of substance abuse treatment and training programs.

Sarasa-Renedo A, Espelt A, Folch C, Vecino C, Majó X, Castellano Y, Casabona J, Brugal MT; Redan Study Group.

Gac Sanit. 2014 Jan 10. pii: S0213-9111(13)00227-6. doi: 10.1016/j.gaceta.2013.10.012. [Epub ahead of print]

Comment: Substance use disorder treatment programs are increasingly engaging in overdose prevention efforts – a badly needed development.

8) Commentary on Kerr et al. (2013): advertising high-potency heroin.

Dietze P.

Addiction. 2013 Jul;108(7):1277-8.

Comment: Interesting remarks by the author, suggesting that rather than advertising the high potency heroin, simply noting a spike in deaths and advertising overdose prevention/response strategies may be safer and more relevant to the target population.

PubMed Update October 2013

A slight reprieve from the onslaught, only 6 articles this month – some of which are really interesting.

1) The Toxicology Investigators Consortium Case Registry-The 2012 Experience.

Wiegand T, Wax P, Smith E, Hart K, Brent J.

J Med Toxicol. 2013 Nov 1. [Epub ahead of print]

Comments: Fascinating TocIC Registry, including cases that were attended to by boarded medical toxicologists (so this would represent a tiny subset of the type of accidental drug overdoses we generally discuss on this site). I’m unable to access the full article.

2) Acute coronary syndrome after methadone overdose in an opiate-naive patient.

De Cuyper A, Lambert M, Hantson P.

Acta Clin Belg. 2013 May-Jun;68(3):250-1. No abstract available.

Comments: Unable to access and no abstract available.

3) Delayed post-hypoxic leukoencephalopathy: case report with a review of disease pathophysiology.

Meyer MA.

Neurol Int. 2013 Jul 22;5(3):e13. doi: 10.4081/ni.2013.e13.

Comments: There was a similar review we discussed in 2012. This is a devastating white matter neurologic disease that has been reported after severe opioid overdoses; tends to occur days to weeks after the event.

4) Revisiting the role of the urban environment in substance use: the case of analgesic overdose fatalities.

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

Am J Public Health. 2013 Dec;103(12):2252-60. doi: 10.2105/AJPH.2013.301347. Epub 2013 Oct 17.

Comments: Fascinating analysis of opioid analgesic overdose fatalities in New York City from 2000-2006, compared to heroin overdose deaths and non-overdose unintentional deaths. Opioid analgesic deaths basically fit in the middle in terms of neighborhood wealth and social structure, between heroin deaths (lower income, socially fragmented) and non-overdose deaths (higher income, less fragmented). This article is also the first academic publication I’ve seen that demonstrates the unique geographic nature of opioid analgesic overdose mortality in NYC – Staten Island is an epicenter, a location that was historically essentially exempt from heroin overdose death.

5) Opioid overdose mortality in kansas, 2001-2011: toxicologic evaluation of intent.

Okic M, Cnossen L, Crifasi JA, Long C, Mitchell EK.

J Anal Toxicol. 2013 Nov;37(9):629-35. doi: 10.1093/jat/bkt085.

Comments: Analysis of opioids in deaths in Kansas, including drug concentrations. The most notable finding is that there is a very wide range of concentrations in overdose deaths involving these agents, a result consistent with decades of toxicological literature suggesting that tolerance plays a big role on risk for overdose and subsequent death.

6) Training family members to manage heroin overdose and administer naloxone: randomized trial of effects on knowledge and attitudes.

Williams AV, Marsden J, Strang J.

Addiction. 2013 Sep 17. doi: 10.1111/add.12360. [Epub ahead of print]

Comments: Authors randomized family members to receive just information versus a 60-minute training. They found that family members who went through the training scored higher on the standardized knowledge and attitude scales authors had previously published. Of note, naloxone was administered in witnessed overdose events for 3 out of 92 who just received information and 5 out of 95 who received the 60-minute training. This raises the very different question of what is sufficient for non-medical personnel to safely and effectively administer naloxone in the community? Information alone may be the answer to that question. While in-depth trainings are fantastic when available and accessible, requiring such activities can easily become an unnecessary obstacle to dissemination of the intervention … perhaps similar to historic requirements for extensive counseling and consent processes prior to HIV testing.

PubMed Update: A Year in Overdose

Here is a summary of our first year of PubMed updates. This list is NOT comprehensive and focuses on opioids at the expense of stimulant issues. There are some excellent papers not listed in the PubMed database (e.g. a couple of great papers out of Scotland we’ve discussed here and many conference abstracts).

So … there were an impressive 81 papers! Basic epidemiology and opioid analgesics dominate, but the list is quite diverse. I’ve roughly categorized papers, but many would fit into multiple categories, and I have not updated the comments …

EPIDEMIOLOGY

1) Drug overdose deaths --- Florida, 2003-2009
Centers for Disease Control and Prevention
MMWR Morb Mortal Wkly Rep. 2011 Jul 8; 60(26):869-72

Comments: Again, oxycodone has arisen as a major source of overdose mortality. The use characteristics that lead to mortality, however, remain unexplained.

2) Characteristics of drug users who witness many overdoses: Implications for overdose prevention.

Bohnert AS, Tracy M, Galea S. Drug Alcohol Depend. 2011 Aug 10.

Comment: Another analysis from a non-fatal overdose survey in Harlem and the South Bronx. There have been some concerning results in terms of witness management of overdose from this study. We know that those who have overdosed are at higher risk of overdose and from a 2005 analysis also know that they are less likely to contact emergency medical services when they witness an overdose. Now we know that these findings apply to those who witness multiple overdoses as well (they appear to be almost the same population). Authors propose that prior negative experiences with medical service might dissuade contact at future overdoses, although perhaps successful prior lay resuscitation efforts also discourage calling for help.

3) Drug-Related Death Following Release from Prison: A Brief Review of the Literature with Recommendations for Practice.

Leach D, Oliver P. Curr Drug Abuse Rev. 2011 Aug 12. [Epub ahead of print]

Comment: I don’t have access to the full article and hope that naloxone distribution is discussed as one of the options.

4) Mortality among Substance-using Mothers in California: A 10-year Prospective Study.

Hser Y, Kagihara J, Huang D, Evans E, Messina N. Addiction. 2011 Aug 10

Comment: Mortality among pregnant or parenting women seeking substance abuse treatment (including heroin, cocaine, alcohol, marijuana, and methamphetamine) over ten years was 8.4x higher than the general population, the largest portion of which was from overdose (29%). The authors do not breakdown overdose by primary drug problem (i.e. can’t tell if most of the overdoses were among heroin users or if they were more evenly distributed).

5) An analysis of the root causes for opioid-related overdose deaths in the United States.

Webster LR, Cochella S, Dasgupta N, Fakata KL, Fine PG, Fishman SM, Grey T, Johnson EM, Lee LK, Passik SD, Peppin J, Porucznik CA, Ray A, Schnoll SH, Stieg RL, Wakeland W.

Pain Med. 2011 Jun;12 Suppl 2:S26-35.

Comment: A review of structural and individual factors related to opioid overdose increases in the U.S.