Abstract
Dear Editor:
Most individuals with cancer pain respond to morphine. However, a significant minority will either fail to have pain relief or will develop dose-limiting toxicity. 1 One of the strategies for managing opioid poorly responsive pain and opioid side effects is to switch opioids. Opioid switches may also be appropriate if a route switch is necessary and the initial opioid (such as oxycodone) is not available parenteral or a switch is needed for reasons of cost. 1 Equianalgesic tables are used as a guide for opioid switches. Opioid equivalents are published ratios of opioid doses which produce the same degree of analgesia. Equianalgesic tables are usually standardized to 10 mg of parenteral morphine. 1 There is an inverse relationship between analgesic potencies and equivalents. For example, fentanyl is 70–100 times more potent than oral morphine and therefore equivalents are 1:70–100 (fentanyl:morphine). Most of equianalgesic tables are derived from single-dose studies. 1 Safety is the most important factor when rotating and secondarily analgesia. Doses of the second opioid frequently need to be adjusted based on the clinical situation. The use of equianalgesic tables can be dangerous if the clinical situation (organ function, age, interfering drugs) is not considered.2,3 There are large numbers of equianalgesic tables published in peer reviewed literature, drug package inserts and within Physician Desk References. 4 The side confidence intervals of equianalgesic ratios are infrequently provided in tables. 5 Conservative equianalgesic ratios in one direction provide an element of safety when used in one direction but are not conservative and increase the risk of opioid overdose when used to switch opioids in the reverse direction. Bidirectional differences in equivalents are known to occur between certain opioids. 3 Populations from whom equivalents are derived can be dissimilar to populations for who opioid rotations are performed which would render equivalents more unreliable than if used in the same population. 3 The degree of incomplete analgesic cross tolerance between opioids influences equivalents and is not predictable in a single individual. Incomplete cross tolerance can develop overtime resulting in a time-dependent shift in relative equivalence between opioids. 3
Morphine: Hydromorphone Equivalents
Original tables had hydromorphone:morphine equivalent ratios of 7.5:60 (by mouth) and 1.5:10 (parenteral). 6 Published variability in oral morphine: hydromorphone ratios range from 40–60:6.5–7.5 to 10:2.5.4,7 Eddy8,9 found a ratio of 1:7 (hydromorphone to morphine) in single oral dose studies and 10:2.5-5 in multidose studies. Lawlor 10 found ratios of 5.3:1 (morphine:hydromorphone) at steady state when given by mouth or parenterally with some bidirectional differences. (1:3.8, hydromorphone:morphine). Four studies that used patient-controlled analgesia (PCA) opioids for transplant-related mucositis found similar ratios.11–14 In two of these studies the ratio between morphine and hydromorphone diminished to 3:5:1 over 2 weeks.11,14 This may have been due to the development of non-cross tolerance over time or the production of the morphine metabolite, morphine-6-glucuronide.
Equivalents can be determined indirectly, through a third opioid. 15 Gagnon and colleagues 16 switched individuals with cancer pain from oral or subcutaneous morphine and hydromorphone to subcutaneous oxycodone. The morphine:hydromorphone equivalence was 5.98:1 (morphine:hydromorphone) with large interindividual differences in equivalence. Wantanbe and colleagues 17 determined equivalence between morphine and fentanyl, hydromorphone, and fentanyl. The fentanyl:morphine ratio was 1:85 and fentanyl:hydromorphone ratio 1:23. The morphine:hydromorphone ratio would be 3.7:1. The authors noted that there were large differences in equivalence.
Based on published experiences of hydromorphone to morphine switches the single-dose equianalgesic ratio is 1:7, the initial steady-state oral and parenteral equivalence is 1:5, and over time with long-term infusions, 1:3.5. This difference may explain why published tables differ in equianalgesic ratios and the disparity between parenteral and oral morphine to hydromorphone equivalents.18,19 Parenteral equivalents may have been derived from single-dose studies whereas oral equivalents were derived from multiple dose studies. 20 This is in contrast to the clinical experience with oral and parenteral rotations in which ratios remain the same regardless of route. 10
The perpetuation of equianalgesic tables without referencing to clinical study design, population and how equivalence were determined (by single dose or at steady state) causes confusion among clinicians who use equianalgesic tables for opioid switches. In addition, equianalgesic tables should have confidence intervals around ratios since there are large differences in equivalents between individuals.3,4 Even if this information is provided, care should be taken to individualize dosage calculations for individual patients, and employ vigorous monitoring for therapeutic response and potential toxicity.
Footnotes
*
A World Health Organization Project in Palliative Medicine.