Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a BS and PharmD. He is a Diplomate to the Academy of Integrative Pain Management, a Fellow to ACCP, ASHP, & FSMB, a member of several other professional organizations. He is CEO of Remitigate (remitigate.com), an opioid safety software development LLC. Dr. Fudin is a section editor for Pain Medicine & Co_Editor-A-Large for Practical Pain Management. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York and has academic affiliations with Western New England University and Albany Colleges of Pharmacy.
Prescribers are often faced with an option to rotate therapy to a different opioid, switching between variable chemical classes of opioids to enhance efficacy and improve patient outcomes with consideration to adverse event profile, analgesic benefits, and patient adherence.1
This is commonplace among skilled prescribers, and the technique has been coined ”opioid rotation”.1 Nevertheless, there are no universal guidelines on converting between opioids. Moreover, online “equianalgesic” opioid dosing calculators may have quite a disparate output in terms of equianalgesic dosing between and among opioids.
Therapeutic conversion of opioids necessitates an important skillset that is sorely lacking. Therefore, the practice requires prescribers and pharmacists to pay careful attention and use good clinical therapeutic judgment and common sense. It is the classic case of where science, mathematics, and experience intersect.
An important consideration in this approach is individualized patient care. Patients have a vast array of individual differences that may relate to pharmacogenetics, drug-drug interactions, drug-food interactions, disease states (with a high importance on hepatic and renal disease), physical attributes, diet, allergies, and previous response or lack thereof to certain drugs within similar pharmacological classes, even if they have a different indication.
A great example is choosing between amitriptyline and cyclobenzaprine, each of which has separate indications, but both of which are chemical tricyclics. The only real difference is a double bond in the middle ring.
Another example is tramadol and serotonin–norepinephrine reuptake inhibitors (SNRIs), both of which have the ability to block the reuptake of norepinephrine and serotonin, but each of which has different indications.
Opioid rotation is appropriate when the patient stops adequately responding to a particular opioid, has never responded, is approaching doses where side effects are starting to limit escalation, and/or other risks such as elevated QTc from methadone.
Once a prescriber determines which opioid to rotate, accurate and safe conversion becomes a conundrum. Because of the significant variability across opioid dosing techniques, it is still unclear what the equianalgesic dose would be.2
A 2013 study published in Practical Pain Management was the first to truly show the significance of this variability when considering online opioid conversion calculators.2
The authors attempted to convert various opioids to their morphine-equivalent daily dose (MEDD) while comparing different online opioid conversion calculators with manual calculations to identify the major disparities among them, as well as the potential dangers those disparities could cause.2
Seven different calculators were included in the study, yielding a total percent variation range from -55% to +242%. The 2 opioids with the greatest disparities were fentanyl and methadone, which had calculated percent variations of 100% and 242%, respectively.2
A more recent publication elucidated this dangerous disparity among opioid conversions regardless of the method used or the practitioner’s background and training. This survey asked physicians, pharmacists, and nurse practitioners (NPs) to convert hydrocodone 80 mg, fentanyl transdermal patches 1800 mcg (75 mcg/hr), methadone 40 mg, oxycodone 120 mg, and hydromorphone 48 mg to their oral MEDD.3
It is important to note that about 70% of the physicians, half of the pharmacists, and 80% of the NPs identified themselves as having specialty training in pain and/or palliative care. Additionally, the respondents could use any resource to convert opioid doses.3
The results showed that the overall mean morphine equivalent doses (+ standard deviation) were 183 (+ 136) mg for fentanyl, 88 (+ 42) mg for hydrocodone, 192 (+ 55) mg for hydromorphone, 188 (+ 122) mg for methadone, and 176 (+ 38) mg for oxycodone. Participants identified using personal knowledge (46%), an online calculator (31%), textbook table (17%), and conversion table from a journal (6%) to properly calculate the conversions.3
Adding insult to injury, consider that methadone prescriptions represent only 2% to 5% of all prescribed opioids, and yet methadone is involved in approximately 30% of all opioid deaths.4
Is this because health care providers don’t know how to convert it? Or because of the drug’s long and variable half-life? Or because there are at least 6 cytochrome enzymes involved in its metabolism? Or because it depends on p-glycoprotein for absorption through the gut and into the central nervous system (CNS)? Or is it a combination of all of these?
Data presented in both of the aforementioned studies demonstrate significant and alarming variability not only in calculating morphine equivalent doses, but also in the resources used. Perhaps the most disturbing variation is the standard deviation values of fentanyl (+ 136 mg) and methadone (+ 122 mg).
Using the lower end of this spectrum in conversion could result in inadequate pain relief, while using the upper end could result in increased frequency and intensity of adverse events and quite possibly opioid-induced respiratory depression and resultant morbidity and mortality. 3
For providers who are asked to convert between these potentially harmful medications quickly, these results are simply not good enough to ensure proper patient care.
Prescribers and pharmacists seem to be swimming in very dangerous waters due in large part to the lack of conversion standards and/or poor understanding of important unique patient variables. Most opioid rotation-related adverse events and deaths are preventable, but many current processes for rotation are flawed.5
Promoting a new paradigm for safe and effective opioid rotation, a 2012 study published in Pain Medicine recommended slowly beginning a downward titration of the original opioid while introducing the new opioid at an opioid-naïve starting dose. The complete conversion should occur over 3 to 4 weeks, using an immediate-release opioid throughout to prevent withdrawal and/or increased pain.6
The bottom line is that all clinicians need to be on the same page when monitoring patients taking opioids. The prescriber must keep a close eye on the patient’s response and side effects, and pharmacists in the community must understand how important a role their counseling can play in preventing opioid overdose and death.
Opioid rotations might impart the perfect opportunity for pharmacists to suggest that a naloxone reversal kit be made available in the home. Together, pharmacists need to keep the opioid conversion ship full steam ahead to avoid the horrifying aftermath of throwing a dinghy out to patients when it’s too late.
This article was collaboratively written with Jeffrey J. Bettinger, a 2017 PharmD Candidate at Albany College of Pharmacy and Health Sciences, with a concentration in Nephrology. He is a volunteer Student Pharmacist engaged in the Stratton VA’s national Opioid Safety Initiative under the mentorship of Dr. Fudin and participates in their VALOR program. His future plans include a general practice residency followed by a specialty practice PGY2 program.
This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.
1. Fine PG, Portenoy RK, et al. Establishing “Best Practices” for Opioid Rotation: Conclusions of an Expert Panel. J Pain Symptom Manage. 2009 September; 38(3): 418–425.
2. Shaw K and Fudin J. Evaluation and Comparison of Online Equianalgesic Opioid Dose Conversion Calculators. Practical Pain Management. 2013 August.
3. Rennick A, Atkinson TJ, Cimino NM, Strassels SA, McPherson ML, Fudin J. Variability in Opioid Equivalence Calculations. (2015) Pain Medicine. In press.
4. Centers for Disease Control and Prevention. CDC features: prescription painkiller overdoses: methadone. http://www.cdc.gov/vitalsigns/methadoneoverdoses/. Accessed September 5, 2015.
5. Webster LR and Fine PG. Review and Critique of Opioid Rotation Practices and Associated Risks of Toxicity. Pain Medicine. 2012; 13: 562–570.
6. Webster LR and Fine PG. Overdose Deaths Demand a New Paradigm for Opioid Rotation. Pain Medicine. 2012 ; 13: 571–574.