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Tuesday, July 29, 2014

Physostigmine: The Drug, The Dogma, and the Real Story

Physostigmine is a reversible cholinesterase inhibitor used in the management of antimuscarinic toxicity.  It differs from pharmacologically similar medications, such as neostigmine and pyridostigmine, due to its tertiary amine structure, which facilitates entry into the central nervous system.  By crossing the blood-brain barrier, we can expect it to be effective for reversal of both peripheral and central signs of the antimuscarinic toxidrome [1].


Inhibition of the cholinesterase enzyme will cause an increase of acetylcholine in the synapse of cholinergic nerve fibers.  As a result, efficacy related to reversal of antimuscarinic toxicity is associated with increased availability of the neurotransmitter at the receptors for competition with xenobiotics blocking those receptors.  In contrast to naloxone and flumazenil which work by direct inhibition of their respective receptors, the indirect mechanism of physostigmine leads to a somewhat complicated evaluation of its pharmacokinetic parameters.  The duration of action of receptor-based reversal agents would be expected to correlate well with the serum half-life of the drug; however, in the case of physostigmine, its duration is much longer and is likely better characterized by the half-life of cholinesterase inhibition.   A study evaluating the pharmacokinetics of physostigmine in patients with Alzheimer’s disease found that the half-life of cholinesterase inhibition (about 80 minutes) was five times that of the plasma half-life (approximately 16 minutes) [2]. Onset of action is delayed by several minutes because efficacy is dependent on accumulation of acetylcholine in the synapse rather than direct receptor blockade. 

An increase in acetylcholine does not come without risk.  We know from experience with other cholinesterase inhibitors (e.g., carbamate insecticides and organophosphates) that excess acetylcholine can be incredibly toxic.  When administered to patients without antimuscarinic toxicity, adverse effects of physostgimine include nausea, vomiting, and diaphoresis [2].  In the setting of overdose where multiple other medications may be contributing to the presentation of the patient, other consequences of acetylcholine may be more concerning.   Acetylcholine released from the vagus nerve binds to muscarinic receptors of the sinoatrial and atrioventricular nodes causing slowed conduction and the potential for bradycardia/bradydysrhythmias [3,4].  Seizures are common with certain cholinesterase exposures and seizure threshold appears lowered due to acetylcholine induced glutamate release [5].

Despite antidotal use dating back to the 1860s [6], recent use of the drug has been limited due to concern for potential adverse effects.  In 1980, a report was published by Pentel and Peterson detailing two cases of physostigmine administration complicated by asystole [7].  Both cases involved severe tricyclic antidepressant toxicity with seizures and significant blockade of cardiac sodium channels manifested by prolonged QRS duration on ECG and a relative bradycardia (both patients with heart rates of 75 beats/minute).  Of note, one patient had also ingested propranolol.  Each patient received physostigmine and subsequently developed bradycardia and asystole. 

So what happened in these patients?  Is this indicative of unpredictable and severe adverse effects related to physostigmine administration or are these expected effects related to increasing acetylcholine in the presence of severe sodium channel blockade?  Both patients had very severe conduction blocks and increasing acetylcholine concentrations in that scenario presumably slowed conduction even further.  The administration of physostigmine likely removed the protective effect of antimuscarinic tone that led to an increase in heart rate despite sodium channel blockade [8].  Additionally, the progression of seizures, severe conduction blocks, and bradycardia is consistent with the natural progression of severe tricyclic antidepressant toxicity resulting in fatalities [9].  It is possible that the patients in that report may have developed asystole even without the administration of physostigmine. 

Concern for seizures is another frequently cited rationale against the administration of physostigmine.  Although severe cholinergic crisis may cause seizures, this would be unlikely to happen in a healthy individual given a normal dose of physostigmine. In fact, this was not reported as an adverse effect in the pharmacokinetic study done in Alzheimer’s patients [2].  Because acetylcholine-induced glutamate release lowers the seizure threshold, it is not surprising that reports of “physostigmine-induced seizures” occur in the setting of overdose with eleptogenic medications [7, 10-11].  Mitigation of seizure risk can be accomplished with co-administration of benzodiazepines in these patients.  In fact, we often use adjunctive benzodiazepines along with physostigmine when neuromuscular excitation is present.

Another argument against physostigmine use is the belief that benzodiazepines are a safe alternative and can provide control of agitation while avoiding the potentially serious adverse effects.  A retrospective study [12] comparing these therapies in 52 patients found that physostigmine reversed delirium in 87% of patients and controlled agitation in 96%.  Benzodiazepines controlled agitation in 24% of patients but did not reverse delirium in any patients.  Time to recovery was shorter in patients treated with physostigmine first (12 hours versus 24 hours; p = 0.04).  Complications were statistically significantly higher in patients treated with benzodiazepines and included intubation, aspiration pneumonia, and delayed recovery.  Cholinergic adverse effects (diaphoresis, emesis, diarrhea, asymptomatic bradycardia, increased secretions) were reported in 11% of patients receiving physostigmine but none developed asystole or seizures.  Despite significant limitations related to the retrospective nature and small sample size, this study gives us data that benzodiazepines are unable to control delirium and may in fact be harmful in the management of antimuscarinic toxicity.

Determining when physostigmine use is warranted can be confusing due to the complex nature of the drug’s pharmacokinetic and pharmacodynamic interactions along with the strong sway of opinion that have marred debate regarding its use since the Pentel and Peterson case report [7] was published.  Due to the short serum half-life, there is often the impression that re-dosing the antidote will be needed and is likely to be frequent.  A retrospective study [13] evaluating this hypothesis found that only 31% of patients received multiple doses.  Interestingly, the longest time reported between doses was approximately 5.5 hours.  The investigators did not evaluate the effect of the initial physostigmine dose or severity of toxicity on the likelihood of receiving multiple doses.

Our toxicology consult service frequently utilizes physostigmine as an antidote and we have administered it in over 120 unique patient encounters since 2011.  We have had no serious adverse effects related to its administration.  It has been effective in reversing agitation/delirium associated with several medications including diphenhydramine, hydroxyzine, clozapine, and promethazine.  We have also found it useful for reversing the coma and delirium associated with cyclobenzaprine, quetiapine, and olanzapine.   Rapid administration has previously been related to adverse effects [1] and does not improve efficacy.  Our protocol involves administration of a 2 mg dose over 10 minutes; the dose is prepared by diluting a 2 mg ampule in a syringe containing 0.9% sodium chloride to a total volume of 10 mL.  We avoid use of physostigmine in patients with significant conduction blocks or those with bradycardia.

Physostigmine is an effective agent in the management of antimuscarinic toxicity and is safe when used appropriately.  Previous reports of asystole after administration have been misinterpreted as a serious and unpredictable side effect rather than an event that may be anticipated in selected patients (e.g. severe tricyclic antidepressant toxicity or those also ingesting a beta blocker).  The case report by Pentel and Peterson made no recommendations regarding the use of physostigmine; however, many clinicians have used the reported effects as a reason for avoiding its use altogether.  At the time of its publication, tricyclic antidepressant intoxication was much more common than it is now and may have called into question a positive risk-benefit analysis. I believe it is important to reconsider this analysis.  We know that severe tricyclic antidepressant toxicity is frequently manifested by rapid onset and progression of coma, seizures, conduction blocks, and hypotension; my conclusion from the oft-cited reports of asystole would be to avoid physostigmine in these patients.  We should be careful not to misinterpret the data presented as rationale for avoiding the use of physostigmine in all patients, as some may benefit from its administration.


Rachel Schult, Pharm.D.
Clinical Pharmacy Specialist, Toxicology
University of Rochester Medical Center
Rochester, New York

References:
  1. Howland M. Antidotes in Depth (A12): Physostigmine Salicylate. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank's Toxicologic Emergencies, 9e New York, NY: McGraw-Hill; 2011:759-762.
  2. Asthana S, Greig NH, Hegedus L, et al.  Clinical pharmacokinetics of physostigmine in patients with Alzheimer's disease.  Clin Pharmacol Ther 1995; 58(3):299-309.
  3. Curry SC, Mills K, Ruha A, O'Connor AD. Chapter 13. Neurotransmitters and Neuromodulators. In: Nelson LS, Lewin NA, Howland M, Hoffman RS, Goldfrank LR, Flomenbaum NE. eds. Goldfrank's Toxicologic Emergencies, 9e New York, NY: McGraw-Hill; 2011: 191-194.
  4. Organophosphates. In: POISINDEX® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically.
  5. Collombet JM.  Nerve agent intoxication: recent neuropathophysiological findings and subsequent impact on medical management prospects.  Toxicol Appl Pharmacol 2011; 255(3):229-41.
  6. Nickalls RWD, Nickalls EA: The first use of physostigmine in the treatment of atropine poisoning. Anesthesiology. 1988; 43:776-779. 
  7. Pentel P, Peterson CD.  Asystole complicating physostigmine treatment of tricyclic antidepressant overdose.  Ann Emerg Med 1980; 9(11):588-90.
  8. Suchard JR.  Assessing physostigmine’s contraindication in cyclic antidepressant ingestions.  J Emerg Med 2003; 25(2):185-91.
  9. Kulig K, Rumack BH.  Physostigmine and asystole.  Ann Emerg Med 1981; 10(4):228-29.
  10. Knudsen K, Heath A.  Effects of self poisoning with maprotiline.  Br Med J (Clin Res Ed) 1984; 288(6417):601-3.
  11. Newton RW.  Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage.  JAMA 1975; 231(9):941-3.
  12. Burns MJ1, Linden CH, Graudins A, et al.  A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning.  Ann Emerg Med 2000; 35(4):374-81.
  13. Rosenbaum C, Bird SB.  Timing and frequency of physostigmine redosing for antimuscarinic toxicity.  J Med Toxicol 2010; 6(4):386-92.                                         

Editorial note:
Physostigmine is one of those drugs that has a very specific and clear indication with several contraindications, making it seemingly more dangerous than it really is. As the case with several drugs (e.g. droperidol, flumazenil, nitroprusside), bias associated with reporting of both successful treatment and complications associated with administration is clearly a factor when it comes to evaluating where these dogmas, as Rachel has described, have originated. One other confounding factor associated with this is the fact that back in the 1970s and 1980s when physostigmine began to gain a bad rap, clinicians did not understand and appreciate the wide range of complications associated with toxicity of tricyclic antidepressants, and as a result, goals for treatment were different than they are now. Although we do know better now, such ideas have affected clinical practice, as it was recently demonstrated that physostigmine is underutilized relative to benzodiazepines in managing anticholinergic toxicity. Prudent use of the drug is key, and when utilized in this manner, it holds much value as an antidote in the emergent and critical setting.

--Nadia Awad, Pharm.D., BCPS (Nadia _EMPharmD)

Wednesday, July 23, 2014

EMPOWER Episode 3 - Pipeline Antidotes for Target Specific Oral Anticoagulants (TSOACs)

Listen to the podcast by clicking on the link below (link to iTunes here):


Show Notes:


Core content from this episode discussed in:
DiPiro's Pharmacotherapy, 9th Edition, Chapter 9
Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Chapter 30

Published articles and references and ongoing trials related to pipeline antidotes for target specific oral anticoagulants discussed during this episode:



  • Aripazine (PER 977):
    • Data from Perosphere available here.  

Wednesday, July 9, 2014

IV Acetaminophen for Pain Management in the ED

One of the most entertaining emergency physicians I work with has fallen head over heels in love with intravenous (IV) acetaminophen. He jokes that he orders the product at least once per shift just to get a “visit” from me. I trade jabs, asking how many golf trips he’s received from the manufacturers of IV acetaminophen (trade name Ofirmev).

I had the opportunity a few years ago to complete a formulary review of the IV acetaminophen product during my pharmacy practice residency. One of the anesthesiologists had requested it for peri-operative use. At the time we suspected that if we added the agent to the hospital formulary (even if it was just for peri-operative use), it would expand to other areas of the hospital and it could have a substantial impact on the budget. We wanted to make sure that if it indeed would have an impact, that it should be offset by its perceived benefit with regard to better pain control and decreasing opioid-related adverse effects.

IV acetaminophen was marketed on the premise that it could serve as a foundation for “multi-modal” pain control by achieving more rapid and higher plasma concentrations than the oral and rectal formulations. Theoretically, this would reduce opioid use and therefore reduce opioid related adverse events. However, this hasn't exactly panned out in clinical studies. A meta-analysis by McNicol and colleagues found a whopping reduction of 1.3 mg morphine equivalent at 6 hours among 154 post-operative patients in whom IV acetaminophen was added. Not surprisingly, they found no decrease in opioid-related adverse events.1 These findings were replicated in another meta-analysis by Remy and colleagues who found a 9 mg morphine equivalent reduction at 24 hours among post-operative patients. Again, there was no difference in opioid-related adverse events between groups.2

So why the disconnect? Pharmacokinetic studies have demonstrated a clear difference between the oral and IV routes of administration (see figure below). Product promotional materials suggest that the threshold for analgesic effects is 16 mcg/ml (or 16 mg/L), and the threshold for antipyretic effects is 5 mcg/mL. However, these thresholds are based on small studies and pharmacokinetic models.3,4 There are numerous trials evaluating escalating doses of acetaminophen achieving higher serum concentrations, but lacking additional analgesic benefit.5-7 These findings were validated in a large Cochrane review of nearly 6,000 surgical patients that failed to demonstrated a clear dose-response relationship.8 Additionally, even though it appears that peak acetaminophen concentrations are reached rapidly with the IV formulation, there is a “lag-time” of at least 60-90 minutes for analgesic effect.9

Some proponents of IV acetaminophen may argue that in patients who are NPO, there aren't really many options for non-opioid pain control, especially when the bleeding risks of parenteral NSAIDs might outweigh any benefit. The rectal formulation of acetaminophen may be dismissed as “simply undignified.” I would argue that it’s equally (if not more) offensive to use a drug that is approximately 50-fold more costly than its rectal form, 13-fold more costly than an opioid, and 1000-fold more costly than its oral form.




What’s worse, the manufacturer of Ofirmev (now Mallinckrodt Pharmaceuticals) recently instituted a price hike of approximately 140% on the product in May 2014. You may say, why the fuss over a $30 dose of a drug? There are a lot more costly interventions they may be subjected to during the course of their visit. Fair enough. However, when you multiply that dose by even a mere 24 hours of therapy for routine use in your ED population over a year’s time, you may be incurring millions of budget dollars for a medication that hasn't demonstrated any clinical advantage over its alternate formulations. I’m certainly not saying there is absolutely no role for this product; I've just been having a difficult time finding its niche in the ED.


Meghan E. Groth, Pharm.D., BCPS (@EMPharmGirl)
Emergency Medicine Clinician, Fletcher Allen Health Care

References:
1)      McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth 2011;106:764
2)      Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005;94:505
3)      Gibb A, Anderson BJ. Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration. Arch Dis Child 2008;000:1-8
4)      Fong L, Chang Y, et al. Open-label 4-period, randomized crossover study to determine the comparative pharmacokinetics of oral and intravenous acetaminophen administration in healthy male volunteers [poster]. 2007 American Society of Regional Anesthesia and Pain medicine (ASRA) Annual Pain Medicine Meeting and Workshops. Boca Raton (FL), 2007
5)      Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy 1991;11:364-369
6)      Beck DH, Schenk MR, Hagemann K, et al. The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study. Anesth Analg 2000;90:431-436
7)      Hahn TW, Mogenson T, Lund C, et al. Analgesic effect of I.V. paracetamol: possible ceiling effect of paracetamol in postoperative pain. Acta Anesthesiol Scand 2003;47:138
8)      Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database of Systematic Reviews 2008, CD004602
9)      Seymour RA, Rawlins MD. Pharmacokinetics of parenteral paracetamol and its analgesic effects in post-operative dental pain. Eur J Clin Pharmacol 1981;20:215, Nielsen JC, Bjerring P, Arendt-Nielsen L. A comparison of the hypoalgesic effect of paracetamol in slow-release and plain tablets on laser-induced pain. Br J Clin Pharmac 1991;31:267


Editorial Note:
IV acetaminophen is the simultaneously the bane of the clinical pharmacists’ existence and one of the main drugs that keep them employed.  Using a drug that makes no meaningful improvement in patient oriented outcomes, yet is orders of magnitude more expensive allows for heated debate and opportunity for “interventions” (I hate that term)- switching IV APAP to PO or PR formulations- which sure does look great on cost saving spreadsheets.

But looking at the data Meghan highlighted echoes the in house data we've analyzed here: IV APAP saves the patient on average 1 dose of their opioid pain management. It’s Tylenol folks. You wouldn't necessarily expect to slide a suppository into the patient and expect to clinically significantly reduce their opioid consumption. So why would we expect any different from the IV formulation of the same drug?

As pain management goes, there are a plethora of issues (oligoanalgesia, abuse, patient satisfaction scores, etc.) none of which are likely solved by IV APAP. This drug is simply not suitable for the ED. Save your pennies for dexmedetomidine or fosphenytoin.


--Craig Cocchio, Pharm.D., BCPS (@EMPharmacyPGY2)

Thursday, July 3, 2014

The New Scheduling of Tramadol: A Step in the Right Direction?

Note: This post has been featured on MedPage Today, with personal commentary provided within the piece.

For those of you who may have missed it on Twitter yesterday, the Drug Enforcement Administration (DEA) has officially classified tramadol as a Schedule IV substance within the United States under the Controlled Substance Act, which will be effective as of August 18 of this year.

You may be wondering, “So, what’s the big fuss about tramadol that led to this decision by the DEA?”


First, let me start off with a little bit about tramadol itself. Tramadol is a synthetic, centrally acting analgesic. It is actually a racemic mixture, where the (+) enantiomer is involved with binding to the mu opioid receptor as well as inhibition of reuptake of serotonin, while the (-) enantiomer is responsible for preventing the reuptake of norepinephrine. Upon ingestion, it is metabolized via CYP2D6 to O-desmethyltramadol, which is an active metabolite that has higher receptor affinity to the mu opioid receptors relative to the parent drug. It was first approved in Europe in the mid-1970s, and it made its way into the United States in 1995 when it was approved by the Food and Drug Administration (FDA).

Prior to its approval, the Drug Abuse Advisory Committee of the FDA did not initially recommend tramadol to be scheduled as a controlled substance due to preliminary human and animal studies demonstrating a low potential for abuse as well as its given history of being utilized extensively in Europe in the couple of previous decades. However, due to concerns for abuse within the United States, an independent steering committee was founded by the manufacturer of tramadol (Ortho-McNeil) to monitor abuse and dependence patterns of tramadol once it hit the market in the United States. At the time, this was the first time such a committee was developed for monitoring the abuse potential of any such psychoactive medication that was approved by the FDA. With this, strict criteria related to how this monitoring was going to take place were developed as well as factors taken into account that would allow for unbiased recognition of abuse.

Within the first three years of approval of tramadol in the United States, members of the steering committee quickly began to realize that patients on tramadol indeed abused the drug, and the commonly cited statistic is the monthly incidence being 2 to 3 cases per 100,000 patients in the first two years following its approval (1). In addition, complications of abuse were also recognized, including both opioid-like and atypical withdrawal following downward titration of the dose as well as abrupt discontinuation of the medication, which accounted for 40% of adverse effects associated with tramadol (2).

Despite these observations, numerous follow up analyses, and petitions from individuals and organizations, nothing was done. Several analyses have been conducted since then, including one performed by the Department of Health and Human Services demonstrating increased prescribing of tramadol relative to opioid analgesics such as hydrocodone and oxycodone from 2003 to 2008 (in 2012 alone, nearly 40 million prescriptions for tramadol were written for patients in the United States). In addition, a staggering growth in the non-medical use and diversion of tramadol has been observed in recent years, and within the United States, over 16,000 visits to the emergency department related to this occurred in 2010. Not surprisingly, the steering committee dissipated in 2005.

However, critical reviews of this issue have been flatly denied by the WHO Expert Committee on Drug Dependence. For this was not a growing issue that was unique to the United States alone; the abuse potential of tramadol has been supported through observations worldwide throughout Europe, the Asian Pacific, and the Middle East (3-9). Peer review comments from this committee, which convened in Geneva just this past June are available, and recommendations regarding the scheduling of tramadol are fairly mixed (10-12). Some have downplayed the potential for abuse and dependence of tramadol, and arguments against scheduling tramadol included reasoning such as reduced accessibility of the drug for those patients in chronic pain. This is creation of a non-issue, as those who have a valid prescription for tramadol for a legitimate medical condition can access the medication. However, some countries placed tramadol under strict control, the most recent being the United Kingdom, where it is now a class C schedule 3 drug, which ironically went into effect this past June.

Several states were proactive and scheduled tramadol as a schedule IV substance, which is currently recognized under state law in ten states. A retrospective review of exposures to tramadol reported to poison control centers was conducted by investigators with comparisons made in two states where tramadol was scheduled as a controlled substance compared to two states where tramadol was not scheduled. The results of the study demonstrated a decrease in reported exposures to tramadol in those two states following its new scheduling status, and in those states where tramadol was not scheduled, the number of reported exposures to tramadol increased by 14% on an annual basis (13).

What changes will we see following this new status of tramadol? Will patterns of abuse and dependence decrease as a result? Will new methods of diversion be created as a result? Will toxic exposures decrease on a national level? Will other countries follow suit with stricter control for prescribing and dispensing of tramadol? The answers to these questions remain to be seen, but this new scheduling of tramadol by the DEA is a step in the right direction.

References:

  1. Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999; 57(1):7-22.
  2. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003; 69(3):233-41.
  3. Radbruch L, Glaeske G, Grond S, et al. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Subst Abus 2013; 34(3):313-20.
  4. Hawkes N. Deaths from tramadol and legal highs reach new highs in England and Wales. BMJ 2013; 347:f5336.
  5. Tjäderborn M, Jönsson AK, Ahlner J, et al. Tramadol dependence: a survey of spontaneously reported cases in Sweden. Pharmacoepidemiol Drug Saf 2009;18(12):1192-8.
  6. Zhang H, Liu Z. The investigation of tramadol dependence with no history of substance abuse: a cross-sectional survey of spontaneously reported cases in Guangzhou City, China. Biomed Res Int 2013; 2013:283425.
  7. Sarkar S, Nebhinani N, Singh SM, et al. Tramadol dependence: a case series from India. Indian J Psychol Med. 2012; 34(3):283-5.
  8. Progler Y. Drug addiction in Gaza and the illicit trafficking of tramadol. J Res Med Sci 2010; 15(3):185-8.
  9. Fawzi MM. Medicolegal Aspects Concerning Tramadol Abuse. The New Middle East Youth Plague: An Egyptian Overview. J Forensic Res 2010; 2:130.
  10. Expert Peer Review 1: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_1.pdf [Accessed 3 July 2014]
  11. Expert Peer Review 2: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_2.pdf [Accessed 3 July 2014]
  12. Expert Peer Review 3: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_3.pdf [Accessed 3 July 2014]
  13. Spiller HA, Scaglione JM, Aleguas A, et al. Effect of scheduling tramadol as a controlled substance on poison center exposures to tramadol. Ann Pharmacother 2010; 44(6):1016-21.

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