Relying solely on conversion tables to decide opioid dose and frequency can be a grave mistake. With this in mind, this author offers a closer look at opioid pharmacology and equianalgesia for drug rotation and route conversion in order to choose the safest pain management program for patients.
When physicians properly utilize opioids, they are safe but they have serious and potentially lethal side effects. Successful opioid use requires adequate knowledge about opioid pharmacology and equianalgesia for the purpose of both drug rotation and route conversion.
Multiple factors like inter- and intraindividual differences in opioid pharmacology may influence the accuracy of dose calculations as does the heterogeneity of study design researchers use to derive equianalgesic ratios.1 Further, equianalgesic tables should only serve as a general guideline to estimate equivalent opioid doses. Lastly, when applying any table, clinical judgement and individual patient characteristics are important to consider.1 In this article, I will attempt to demystify the calculation of opioid conversion and present important basic mathematical and patient parameters that podiatric clinicians must understand in order to safely and successfully transition patients between pain management regimens utilizing opioids.
Current Practices In Opioid Selection: What You Should Know
The Centers for Disease Control and Prevention (CDC) developed guidelines for primary care clinicians treating adult patients for chronic pain in outpatient settings.2 When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids at the lowest effective dosage instead of extended-release/long-acting (ER/LA) opioids. While advisable to exercise caution when prescribing opioids at any dosage, one should carefully reassess the individual patient’s risks and benefits when considering increasing the dosage to greater than or equal to 50 morphine milligram equivalents (MME) per day. Additionally, one should avoid increasing dosage to greater than or equal to 90 morphine milligram equivalents per day, or carefully justify a decision to titrate dosage to that level.2
Long-term opioid use often begins with treatment of acute pain. When using opioids in these circumstances, clinicians should also prescribe the lowest effective dose of immediate-release opioids in no greater a quantity than necessary. Three days or less will often be sufficient, and more than seven days is rarely necessary.2
While there is no completely safe opioid dose, a patient’s cumulative morphine equivalent daily dose (MEDD) is one indicator of potential dose-related risk for adverse drug reactions to opioids, including overdose.3-5 The terminology for daily morphine equivalency may vary depending on the resource with terms including morphine equivalent daily dose, morphine equivalent dose or morphine milligram equivalent. Daily morphine milligram equivalents address the comparative potency of different agents but do not convert a particular opioid dosage from one product to another.
The calculation to determine morphine milligram equivalents (MME) includes drug strength, quantity, days supply and a defined conversion factor unique to each drug. By converting the dose of an opioid to a morphine equivalent dose, a clinician can determine whether a cumulative daily dose of opioids approaches an amount associated with increased risk. Equianalgesic dose ratios are only approximations and do not account for genetic factors, incomplete cross-tolerance between various opioids and variable pharmacokinetics that may affect relative potency. If using morphine milligram equivalents to estimate a conversion, one should reduce the prescribed dose by 25 to 50 percent after calculating the appropriate conversion dose to ensure patient safety.3-5
Lower extremity specialists can play an important role in averting opioid overutilization or overdose by paying attention to morphine equivalent dosing. Morphine equivalent dosing determines a patient’s cumulative intake of any drugs in the opioid class over 24 hours in an effort to help reduce the likelihood of overdose.3-5 Morphine milligram equivalent is a value assigned to opioids to represent their relative potencies.3-5 Determination of this value uses an equivalency factor to calculate a dose of morphine that is equivalent to the ordered opioid.3-5 Daily morphine equivalent dose is the sum of the morphine milligram equivalent of all opioids a patient is likely to take within 24 hour and that total determines if the patient could potentially near a dangerous threshold.3-5
Along with the strategies employed by morphine milligram equivalent prescribing thresholds, the CDC has provided a checklist for opioid prescribing along with additional tools to guide clinicians on implementing the recommendations.2 One of the tools all clinicians should use when prescribing opioids is the process of opioid conversion calculations. This being said, the process of calculating opioid equivalence may not be uniform between clinicians.
Pertinent Principles In Opioid Rotation And Equianalgesia
Over the last 20 years, opioid rotation, also referred to as opioid switching, has become a common practice for optimizing pain management in chronic pain therapy, oncology, palliative care and post-surgical care. This could be a switch from one opioid to another in an effort to improve therapeutic response or, in some professional circles, is the practice of converting a patient from one opioid to another as clinical circumstances warrant.6-8 These circumstances may include poor analgesic efficacy, intolerable side effects, opioid toxicity, need for a different route of administration, need for a different formulation (e.g. once-daily dosing), different pharmacokinetic properties (route of excretion) and cost considerations.9-10
In any case, opioid rotation calls for approximate equianalgesic conversions that can be problematic based on individual patient response and conflicting data. This may be especially true when this conversion involves more than one opioid analgesic. There is a variety of published conversion tables to provide clinicians a rough guide for making calculations when switching between different opioid routes or preparations, and when determining equianalgesia.8,9,11,12 However, one should understand these published values in equianalgesic tables are only a rough guide as physicians need to consider substantial inter-individual variation. The final prescribed dose needs to take into account a patient’s age; renal, pulmonary and hepatic function; the patient’s current pain level and opioid side effects such as sedation; and prior and current opioid use. The final decision on which opioid or which dose to prescribe must involve a thorough clinical assessment to minimize the risk of prescribing inappropriate opioid doses over or under the patient's actual need.
Podiatric physicians may face the need to change opioid analgesics during the course of their patient's care. The act of converting opioid analgesics, for physicians who do not receive adequate training, remains a challenging and often uncomfortable aspect of pain treatment.6 Part of the challenge clinicians face is that there is relatively weak evidence in the literature to support the equianalgesic ratios provided in textbooks, journals and other medical resources.6 Although dose tables generally determine the new opioid doses, the evidence to support the ratios in these tables largely refers to single dose administration.7,9
Demystifying Opioid Conversion With Example Calculations
Analgesic equivalence is central when considering opioid substitution.7,8,12-16 Opioid substitution and rotation are grounded in the use and understanding of morphine milligram equivalents (see “A Guide To Opioid Equivalency For Common Opioids” above). One calculates these morphine milligram equivalents using conversion factors (see “Calculating Morphine Milligram Equivalents (MMEs)” above). This will help to avoid tolerance, dependency and misuse as well as abuse. One may employ two types of opioid rotation strategies: a change in opioid product or a change in the route of administration.
The following are clinical exercises for using morphine milligram equivalents involving examples of complicated postoperative patients.
Addressing Post-Op Pain Management After Reconstruction For Crush Injuries And Fractures In The Feet
RL is a 59-year-old female with crush injuries and fractures involving both feet. She is admitted for surgical intervention and reconstruction. Postoperatively, her surgeon prescribed 1 or 2 mg of hydromorphone intravenously every four hours as necessary for severe pain (using a visual pain analog scale).
Day one: RL received a total of 12 mg of hydromorphone intravenously over 24 hours.
Day two: RL received 11 mg of hydromorphone intravenously over 24 hours.
Day three: RL received 8 mg of hydromorphone intravenously over 24 hours. She now reports pain levels between 2 and 3 (mild to moderate) after taking the drug.
Day four: Upon preparation for discharge, the foot and ankle surgeon notes RL has a history of itching from ingestion of both oxycodone and morphine. Further, RL reports that oral hydromorphone was effective in the past.
Step one. Recognize that RL used less intravenous hydromorphone on day three than on day one. Therefore, one can reasonably argue that there was good pain control with hydromorphone. Moreover, RL has used oral hydromorphone in the past with effectiveness in controlling mild to moderate pain symptoms.
Step two. Recognize that RL has a total daily dose (TDD) of 8 mg of intravenous hydromorphone over 24 hours on day three.
Step three. Determine a possible oral hydromorphone dose by using algebra to calculate an equianalgesic dose for hydromorphone.
Calculate equianalgesic dose where X is the unknown dose:
X mg TDD oral HM = 7.5 mg oral HM
8 mg IV HM 1.5 mg IV HM
X = 40 mg
Step four. RL is improving every day with pain control and her postoperative hydromorphone regimen. One can expect that a reduced dose requirement will follow in subsequent days. Oral hydromorphone products are available as 2 mg, 4 mg and 8 mg tablets. Consequently, the surgeon could write an initial prescription for hydromorphone tablets (4 mg every four hours as necessary for moderate to severe pain) with an expectation of a requirement of 24 mg of hydromorphone as a total daily dose for RL.
Converting Short-Acting (IR) To Long-Acting (ER) Medication For Well-Controlled, Chronic Pain
MJ is a 47-year-old Hispanic male with chronic lower extremity pain. He received a prescription for immediate release oxycodone/acetaminophen 10-325 mg three weeks ago, and is returning to the clinic for a follow-up appointment.
He states that his pain is generally well controlled but that it tends to reoccur around one hour before his next scheduled dose. He is currently taking two oxycodone/acetaminophen 10-325 mg tablets every four hours around the clock.
20 mg oxycodone (two tablets x 10 mg) x six times/day = 120 mg oxycodone IR in 24 hours
Equivalent extended release dose = oxycodone extended release 60 mg every 12 hours One calculates this by appreciating both tables above. One uses both tables to determine morphine milligram equivalents and then applies an algebraic equation similar to the first example, solving for X, the unknown daily dose of oxycodone.
One may also choose to add an opioid rescue dose for breakthrough pain at 10 to 20 percent of the daily dose. (Range = 10 to 20 percent of 120 mg) = 12 to 24 mg based on immediate release dose.
Answer: Oxycodone ER 60 mg every 12 hours with oxycodone IR 10 to 20mg every four to six hours as necessary for breakthrough pain.
When A Patient Can No Longer Swallow Oral Medication
TDM is a terminally ill lower extremity bone cancer patient with pain well controlled on morphine extended-release 90 mg every 12 hours. He is now unable to swallow so a physician is seeking to convert the patient’s morphine need into a fentanyl transdermal patch.
Step one. The goal is to calculate the hourly dose of the fentanyl patch.
Step two. Calculate the total dose of oral morphine over 24 hours. Ninety mg every 12 hours is 180 mg over 24 hours.
Step three. Convert to the equivalent dose of fentanyl by dividing total 24 hour oral dose by 100 (180 mg / 100 = 1.8 milligrams of fentanyl in 24 hours = 1800 micrograms of fentanyl). Divide the calculated 24-hour dose of fentanyl by 24 to calculate the hourly dose of fentanyl (1800 micrograms / 24 = 75 micrograms of fentanyl per hour).
Answer: Apply a 75 microgram fentanyl patch concurrently with the last dose of long-acting oral morphine 90 mg. Stop the long acting oral morphine after applying patch.
Problems And Pitfalls Of Opioid Equianalgesic Tables
Opioid equianalgesic dosing is not just about the math. Podiatric physicians must depend on the patient’s report and his or her own assessments and experience when making opioid rotation judgements. Equianalgesic dose is that dose at which two opioids (at steady state) provide approximately the same pain relief. Usually, equianalgesic doses standardize to 10 mg of parenteral morphine. Opioids do not have a ceiling effect nor uniform therapeutic plasma levels. For example, there is no clear linear relationship between methadone dose and respiratory depression. Titration is often limited by opioid-induced side effects, constipation, respiratory depression or neurological problems. Furthermore, inappropriate application of a conversion table can result in poor pain control, excessive side effects and death from respiratory depression.
Equianalgesic tables fail to standardize to a reference opioid (usually morphine) and fail to address bidirectional differences between certain opioids. These tables also include of a wide range of doses in equianalgesic comparison, which results in confusion and inaccuracy. Some calculations erroneously use equianalgesic tables as references for other tables. Another drawback is equianalgesic dosing between short and long-acting opioids is not determined at steady state.8 Equianalgesic tables also do not address gender differences, organ dysfunction, drug interactions and individual differences in pharmacokinetics/pharmacodynamics as well as incomplete cross-tolerance.8
There are no evidence-based recommendations for the appropriate reduction when converting one opioid agent to another opioid analgesic agent. Some pain experts recommend a dose reduction between 25 and 50 percent when converting between different opioids.8-13 Acknowledging these challenges, an expert panel concluded there would be value in pursuing the development of more sophisticated equianalgesic tables that incorporate a guideline for dose adjustment based on factors that could influence relative potency.8
Clinically, the podiatric physician needs to consider factors such as patient demographics, opioid receptor affinity and opioid metabolism when selecting an opioid agent for rotation. Equianalgesia tables are useful in routine practice and providers must continue to use them while considering their inherent limitations. The development of clinical trials to evaluate potency of opioid analgesics are still necessary so pain management may continue to evolve. Further studies are necessary in order to refine the equianalgesic dose tables and guidelines for dose conversions, and improve outcomes associated with clinical opioid rotation.
Dr. Smith practices in Ormond Beach, Florida and recently became the Chairman of the Podiatric Medicine Academy, part of the National Academies of Practice.
- Shaheen PE, Walsh D, Lasheen W, Davis MP, Lagman RL. Opioid equianalgesic tables: are they all equally dangerous? J Pain Symptom Manage. 2009;38(3):409-417.
- Centers for Disease Control and Prevention. CDC Guideline for Prescribing Opioids for Chronic Pain. Promoting Patient Care and Safety. Available at: https://www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf . Accessed August 24, 2020.
- Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152(2):85-92.
- Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49.
- Washington State Agency Medical Directors’ Group. Interagency guideline on prescribing opioids for pain. Available at: http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf. Published June 2015. Accessed August 24,2020.
- Ashby MA, Martin P, Jackson KA. Opioid substitution to reduce adverse effects in cancer pain management. Med J Aust. 1999;170(2):68-71.
- Mercadante S. Opioid rotation for cancer pain (rational and clinical aspects). Cancer. 1999;86(9):1856-1866.
- Fine PG, Portenoy RK, Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing “best practices” for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage. 2009;38(3):418-425.
- Anderson R, Saiers JG, Abram S, Schlicht C. Accuracy in equianalgesic dosing conversion dilemmas. J Pain Symptom Manage. 2001;21(5):397-406.
- Knotkova H, Fine PG, Portenoy RK. Opioid rotation: the science and the limitations of the equianalgesic dose table. J Pain Symptom Manage. 2009;38(3):426-439.
- Gammaitoni AR, Fine P, Alvarez N, McPherson ML. Clinical application of opioid equianalgesic data. Clin J Pain. 2003;19(5):286-297.
- Pereira J, Lawlor P, Vigano A, Morgan M, Bruera E. Equianalgesic dose rotations for opioids: a critical review and proposals for long term dosing. J Pain Symptom Manage. 2001;22(2):672-687.
- Smith HS, Peppin JF. Toward a systemic approach to opioid rotation. J Pain Res. 2014;7:589-608.
- Smith RG. A review of opioid analgesics frequently prescribed by podiatric physicians. J Am Podiatr Med Assoc. 2006;96(4):367-373.
- Smith RG. Opioid prescribing: podiatric implications. Podiatry Management. 2018;37(5):161-169.
- Macpherson RD. Pharmacological basis of contemporary pain management. Pharmacol Ther. 2000;88(2):163-185.
- Centers for Disease Control and Prevention. Calculating Total Daily Dose of Opioids For Safer Dosage. Available at: https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf. Accessed August 24, 2020.