Long-term alcohol or drug use can lead to rhabdomylosis.  I don't know all the mechanisms, but found this article abstract:  The medical complications of drug addiction and the medical assessment of the intravenous drug user: 25 years later. http://www.ncbi.nlm.nih.gov/pubmed/8214979  (You need a subscription to access the full article)

and a full-text article: Cocaine use and kidney damage, Fokko J. van der Woude

http://ndt.oxfordjournals.org/content/15/3/299.full

You have to check the diff diagnosis as there are many potential causative agents for rhabdomylosis, ranging from statins to SSRIs to autoimmune issues.  My guess is that you will find, as suggested above, that it is not opioid use directly causing rhabdo, but rather secondary effects, such as Hep-C, etc.  What do you mean by "severe" rhabdo?  Some sort of really acute muscular deterioration occurring in a very short time period?  How long do the patients wait to present?  Do you run blood tests to confirm the urine tests?  I think this is a very interesting finding, but it's hard to guess as to whether it is related to pt SUD without a full differential diagnosis.

Thanks for your help.  These are young men, often returning to the ER a day or two after discharge from hospital or psychiatry units.   Values in the 10,000 to 100,000 range, sometimes leading to dialysis.  The UDS is completely negative for benzo's, opiates, PCP, LSD, buprenorphine, heroine, oxy, etc.  Does not sound like they are out/obtunded for a long enough time to generate this level of dehydration and rhabdo.  Alcohol is negative on presentation.  Wondering if there is something on the street that can do this that is no picked up by regular screens?  GHB? ecstasy? synthetics? Tramadol OD?

Given the extremely high values and acute nature, I would guess it is actually discontinuation of some med they were on in the hospital -- after all, pts are presenting within 48 hours of discharge.  Have they just discontinued buprenorphine?  Intuitively, it sounds more like discontinuation than an immediate side-effect of a substance obtained on the street.  It would take an awful lot of tramadol to generate the symptoms you report.  Have *any* of the patients self-reported using any non-prescribed substances?  I would look at what they were on in the hospital and see if withdrawal could induce dehydration and rhabdo.  If they're young, very unlikely that opioids are cause, primary or secondary.  

Will have to go back and look for some other clues in the med record. Wasn't really thinking of discontinuation syndromes as a cause.  Frightening to see 30 yr olds end up on dialysis!

Hi Patricia,

Opioid overdose can cause drug-induced rhabdomyolysis;

Blain et al Hum Toxicol. 1985 Jan;4(1):71-4.

Opiate-induced rhabdomyolysis

http://www.ncbi.nlm.nih.gov/pubmed/3988309

However I most commonly encounter drug-induced rhabdomyolysis in patients suffering acute psychostimulant toxicity, (typically methamphetamine).

If the patients who prompted your question are only out of hospital for 24 to 48 hours, and are presenting with negative urine tests, that rules out the common opioids and psycho-stimulants. Out of interest, do you use a standard immunoassay screen, or can you have some samples subjected to LC-MS?

Given the short time frame and the negative urine screen results, the symptoms may be the result of some form of discontinuation syndrome, as Devin suggests. However if there are a cluster of these cases in patients with a history of non-medical substance use, I would suspect novel synthetic substances could be involved. Relapse to drug use within 48 hours of hospitalization and enforced abstinence is very common. Even people intending to maintain abstinence frequently relapse once they return to their normal environment.

There are many classes of novel synthetic drugs that will not show up in a standard urine screen for drugs-of-abuse, but which can cause electrolyte disturbances, dehydration, and rhabdomyolysis.

Substituted cathinones, novel synthetic hallucinogens (eg 251-NBOMe,), novel dissociatives (methoxyketamine), piperazine derivatives (such as BZP), synthetic cannabinoids and synthteic opioids have all been associated with rhabdomyolysis.

http://www.nature.com/nrneph/journal/v10/n6/fig_tab/nrneph.2014.44_T1.html

Although you state these patients had a previous history of opioid misuse, in my experience poly-drug use is the norm, (or at least it is far more common than it was 20 or 30 years ago), so it may be other classes of drugs that are responsible. Further, people with a long history of dependent use of opioids who give up do often "switch" to using another class of drug, (especially as an initial "coping strategy" when they are first getting used to being completely abstinent from opioids). Finally, if there is any reason these particular patients would expect to be urine tested, this may have encouraged some of them to use drugs that are not detected by the test.

ED presentations involving substituted cathinones (such as MDPV, MMCat, α-PVP) frequently involve rhabdomyolysis. It appears toxic doses of these stimulants are significantly more likely to result in rhabdomyolysis than cases of cocaine or methamphetamine toxicity.

See; O'Connor et al, J Med Toxicol. 2014 Dec 3.

Prevalence of Rhabdomyolysis in Sympathomimetic Toxicity: a Comparison of Stimulants.

http://www.ncbi.nlm.nih.gov/pubmed/25468315

.

Synthetic cannabinoids are very common and are also associated with acute kidney injury. The vast majority of these will not react in the standard urine screens;

See; Thornley-Brown et al CJSN 2012

AKI Associated with Synthetic Cannabinoids: A Case Series

http://cjasn.asnjournals.org/content/early/2012/12/12/CJN.05690612.short

.

Finally, a number of illicitly produced synthetic opioids have begun to appear on the black market over the last 5 years or so. Some are analogues of fentanyl, but some are entirely novel and would not be detected in any urine screen (and maybe not even by LC-MS if there is no reference for that substance yet). These do not appear to be as prevalent as the novel cathinones and cannabinoids, but could perhaps also be a causal factor?

http://www.emcdda.europa.eu/publications/2015/new-psychoactive-substances

.

 Hope this is helpful.

Regards,

Paul.

Paul - do you think that buprenorphine discontinuation (abrupt) could cause the symptoms Patricia is seeing in her population?  I think it is unlikely that an entire cluster of patients are using exotic synthetic opioids that induce rhabdo.  But I agree strongly that patients frequently relapse within 24-48 hours after discharge, and after reading the O'Connor 2014 article it seems like stimulants could produce the symptoms she has reported.  But these are SEVERE rhabdo cases, with concurrent dehydration.  I haven't heard of anything else like this occurring in a cluster near a particular inpatient treatment center, which is why I was trying to guess as to what the treatment center was doing.  Putting the negative tox screen aside (this is very puzzling) - I am having a hard time thinking of any substance that could produce the symptoms reported in such a cluster and with such *magnitude* - multiple pts going on dialysis 48 hours after discharge from residential AT - have you EVER heard of anything like this?   These patients aren't coming in with OD symptoms, and they don't seem to be coming in with withdrawal symptoms (dehydration yes, rhabdo no).  My first guess was buprenorphine withdrawal as that is often used for inpatient treatment, and the transitions are sometimes not managed carefully.  But if that were true, the patients would be showing signs of acute detox, and I can't find any evidence out there that acute opioid detox (from buprenorphine or any other opioid) will induce rhabdo.  But if it is some mystery opioid (or other substance) causing the symptoms, one would expect at least one or two of these patients to self-report use of same -- this doesn't seem to be the case.  This is really quite a puzzle!

Hi Devin,

Nice to bump into you again! Hope you are well.

The symptoms of abrupt buprenorphine discontinuation syndrome are very similar to the symptoms of abrupt withdrawal from any other opioid. (See attached PDF). Also, bupe is quite long acting, so the severe opioid withdrawal symptoms don't usually emerge until 48 hours or longer after the last dose.

There have been a handful of cases reported where parenteral misuse of buprenorphine tablets or injecting use of sub-lingual tablets has been associated with rhabdomyolysis.

http://www.annemergmed.com/article/S0196-0644%2806%2900081-3/abstract

.

I can't see the full text. My educated guess would be that these cases might possibly be a result of insoluble particles of pill-base (in the case of Subutex or Suboxone, the base is largely maize starch) not being filtered out of the solution prior to injection rather than any pharmacological effect of buprenorphine. The cascade of insoluble particles might compromise kidney function or cause injury to other organs that leads to muscle breakdown. Can't find any similar cases associated with Suboxone sub-lingual films, but they form a goopy mass when dissolved for injection and so could possibly cause similar effects.  However if this scenario were responsible for rhabdomyolysis in Patricia’s patients, I would expect them to test positive to buprenorphine.

Alternatively, rhabdomyolysis amongst people who inject Subutex or Suboxone pills or films might be secondary to a serious non-viral infection. In this cohort, infected abscess at the injection site is not uncommon, especially when the person has not filtered out the maize starch and has then "missed" the vein. This results in the solution sitting in the soft tissue around the vein, and it often goes septic (water + corn flour = gravy). This can lead not just to an abscess at the site, it can also can cause systemic infections “downstream”, such as infective endocarditis (causative agent is typically commensal strains of staph), endophthalmitis (typically commensal candida), or osteomyelitis (typically commensal strains of staph, strepp or other bacteria).

If this was the case with Patricia's patients there would be evidence of serious bacterial infection as a contributing cause, and that infection would probably have been entrenched for much longer than 48hrs. 

Rhabdomyolysis appears to be a very rare ADR from bupe;

http://factmed.com/study-BUPRENORPHINE%20HYDROCHLORIDE-causing-RHABDOMYOLYSIS.php

Are there any other medications that may have been common to this group of patients, and that they would have been withdrawn from on discharge from hospital? If not, I would be suspecting non-medical use of a substance that is not detected in your urine screens and that can cause these acute symptoms within 48 hrs.

Some of the synthetic cannabinoids and the substituted cathinones I mentioned above fit this profile, and the NBOMe series of hallucinogens can also cause rhabdomyolysis.

All of these products are frequently sold in packaging that does not list ingredients or that misrepresents their contents, and the dose or even the ingredients present in some of the branded products varies immensely from batch to batch. Accidental toxicity is a not infrequent result. The NBOMe series have a long onset of action (~90mins before any effect is felt) and it is suspected that many accidental poisonings are a result of someone taking a dose, waiting an hour or more and feeling no effect, and then taking a second dose before the first has had effect, ("toxic re-dosing").

My understanding is that both MDPV and α-PVP are pretty widely available in the US, (both were common ingredients in "bath salts", and α-PVP is often sold now under the names "Flakka" or "Gravel"). Mephedrone (4-MMC) and these other two cathinones are also frequently misrepresented as MDMA (Ecstasy or "Molly"). These sorts of substituted cathinones are frequently associated with acute kidney injury and rhabdomyolysis.

Regards,

Paul.

Paul - good to see you on here as well.  I think you're probably right that it is bath salts.  But, if the residential treatment center is releasing pts with, say, a months supply of 8mg bupe sublingual tabs, then pts taking ALL of them at once could induce rhabdo. Unlikely, though.   Here's the full text of the article you referenced...

Thanks Devin,

I don't have institutional access, so I always appreciate it when someone forwards a full-text.

:)

In both the case histories in that article, the symptoms had emerged reasonably quickly, with both patients presenting within 2 or 3 days of experiencing pain and muscle weakness. Blood tests were negative for any of the sorts of non-viral infections I mentioned above.

>

So it would appear that the most likely aetiology in both cases is that either the buprenorphine itself, or else the base, binders  and other excipients that make up the tablet, caused the severe myositis and rhabdomyositis these two patients experienced.

>

Neither case mentions the person taking large doses.

However myositis and rhabdomyositis appear to be very rare outcomes of injecting misuse of buprenorphine.

In my work I have frequently encountered individuals who misused "Subutex" and "Suboxone" pills and films intravenously.

I've seen many cases of injury caused by insoluble particles in people injecting pharmaceuticals that were designed to be swallowed, such as pulmonary talcosis.

We had an outbreak of endophthalmitis caused by candida infection amongst a cohort of patients who were all smuggling Subutex pills from supervised dosing and injecting them, (so the pills had been contaminated with the fungi whilst in someone's mouth).

And as I mentioned above septic abscess at the injection site, infective endocarditis, and osteomylitis are all reasonably common amongst people who inject buprenorphine pills. Amongst people who inject buprenorphine films pulmonary embolism and infarction are not uncommon. However I've never seen or heard of any cases of rhabdomyolysis associated with injecting buprenorphine, and the ADR doc I linked to above only identified three cases in the literature, so I would be very surprised if this is responsible for the cluster of cases that prompted Patricia to pose this question.

Patricia,

I am really intrigued by your question.

I hope you manage to work out what is responsible for these cases. My first step would to see if any of the patients will admit to use of "legal highs", "Spice", "Gravel" etc, as I suspect synthetic cannabinoids or substituted cathinones are the most likely candidates if street drugs are responsible.

If the hospital will pay for LC-MS testing of urine samples, you might detect these sorts of novel substances, but many of the newer ones have no reference as yet and so would probably return a negative result.

Paul.

Patricia I too am really perplexed by your original question. While Paul is probably right, it's hard to quantify that probability. Please let us know if you do figure it out! [i just got back from dinner with some academic addiction physicians in New York and raised this as it came in on my email during dinner) -- they too had never heard of anything like it, nor did they have any ideas that haven't come up in this discussion.