Opioid Equivalency


Article Author:
Mamta Bhatnagar


Article Editor:
Jennifer Pruskowski


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Trevor Nezwek
Radia Jamil
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Saad Nazir
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Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
12/19/2018 7:33:11 AM

Indications

Opioids are often prescribed for cancer-related pain and moderate-to-severe chronic pain, especially pain inadequately controlled with non-opioid strategies. The goal of this article is to help clinicians learn how to choose and dose opioids in opioid-tolerant patients eligible for opioid rotation.

Mechanism of Action

Mu Receptor Agonists: Dosing Challenges

The majority of clinically useful opioid analgesics bind primarily to mu opioid receptor sites where they have agonist effects. Examples of these mu receptor agonists include morphine, hydromorphone, fentanyl, oxycodone, hydrocodone, and methadone. Because they act on the same receptor, these drugs are theoretically interchangeable, provided the doses are adjusted for relative potency. 

Administration

Routes for common opioids include intravenous (IV), intramuscular (IM), subcutaneous (SQ), Oral (PO), and transdermal (TD). Intramuscular administration is not recommended for pain management while the use of the SQ route is limited to circumstances such as lack of availability of IV. The most common routes of administration of opioids are PO, IV, and TD. Oral short-acting opioids are dosed 3-4 hours apart due to their short half-life. Stable patients on chronic opioid therapy benefit from preventive analgesia and often have regimens that combine a long-acting opioid, dosed 8-12 hours apart, and a short-acting opioid, the latter being used as a breakthrough opioid when pain transiently increases in intensity above the pain addressed by the ongoing analgesics. Intravenous opioids are generally dosed for acute relief of pain in situations where an oral opioid is ineffective, or the oral route is unavailable. Intravenous opioids are dosed 2-3 hours apart or can be dosed as a continuous infusion or as patient-controlled analgesia (PCA). 

Adverse Effects

Adverse effects are common during opioid therapy. In particular, patients on opioids should be monitored for constipation, nausea, vomiting, sedation, impaired psychomotor function, and urinary retention. Among gastrointestinal side effects, opioid-induced constipation (OIC) affects between 45 and 90% of patients[1]and is a source of significant morbidity. It is the most prevalent reason patients avoid or discontinue opioids and can often result in increased length of hospital stay and overall healthcare costs.[2][1][3][4][5][6] Nausea is seen most commonly at the start of therapy. Patients commonly develop tolerance to the emetic effects, so that within 3-7 days, at a constant opioid dose, the emetic effects abate. While there is no research on this effect, morphine and codeine are often mentioned as the worst offenders.

Opioids also have neuroexcitatory effects that might not be easily recognized. Myoclonus is typically a herald symptom. Myoclonus – the uncontrollable jerking and twitching of muscles/muscle groups – most frequently occurs in the extremities, initially presenting with only an occasional random jerking movement.  Myoclonus can present in patients on chronic therapy with most opioids including hydromorphone, morphine, and fentanyl.  Higher doses more frequently result in myoclonus, but the dose relationship is variable.[7]  Myoclonus can occur with all routes of administration. As myoclonus worsens, patients may develop other neuroexcitatory signs: hyperalgesia (increased sensitivity to noxious stimuli), delirium with hallucinations, and eventually grand mal seizures. Treatment usually involves decreasing the opioid dose, opioid rotation or addition of a benzodiazepine.

Sedation occurs in 20-60% of patients,[8] most commonly when initiating opioid therapy or when doses increase. Mild-to-moderate sedation is usually self-limiting, resolving in a few days. If persistent, it may improve with drug therapy.[9] Moderate-to-severe sedation responds to dose reduction, but may also necessitate opioid rotation.

Both pruritus and urinary retention are rare side effects. A combination of topical agents and/or systemic low dose opioid antagonists are commonly used to treat pruritus. Acute urinary retention needs urgent medical attention; if it is thought to be related to the opioid, either the opioid dose can be reduced, or the agent discontinued.

Contraindications

The mu receptor agonists also differ in their metabolism and organ dysfunction can influence their side effect profile. For example, in patients with renal impairment,[10] fentanyl, oxycodone or methadone are preferred whereas for patients with severe liver disease, morphine and hydromorphone are the favored agents.[11]

Monitoring

All patients on chronic opioid therapy regimens require monitoring for continued efficacy as well as an indication for treatment. Monitoring includes a thorough pain assessment that takes into account pain levels, change in the quality of pain, pain recurrence and side effects from analgesics. When a decision is made to rotate to a different opioid, there are essential pharmacokinetic principles to consider: equianalgesia and incomplete cross-tolerance.

Equianalgesia and Incomplete Cross-tolerance

The term equianalgesia, meaning “approximately equal analgesia,” is used when referring to the doses of various opioid analgesics that are estimated to provide the same pain relief. Equianalgesic dose calculations are a means for selecting the appropriate initial dosing when changing from one opioid agent or route of administration to another. An equianalgesic chart provides a list of analgesic doses, both oral and parenteral, which approximate each other in their ability to provide pain relief (i.e., the equianalgesic units). The equianalgesic chart (Table 1) lists rough estimates; individual patients may vary. Morphine is considered the gold standard; hence all calculations occur in Oral Morphine Equivalents (OME).

Most patients on chronic opioids develop tolerance to analgesic and non-analgesic effects of opioids such that a previously effective dose gradually loses efficacy. This is usually manifested as a shortened duration of action and often requires dose escalation to maintain adequate analgesia. Cross-tolerance is the development of tolerance to the effects of pharmacologically related drugs, particularly those that act on the same receptor site. However, when switching to another opioid, it is very important for clinicians to assume that cross-tolerance is incomplete, which means that the starting dose of the new opioid must be reduced by at least 50% of the calculated equianalgesic dose to prevent overdosing. 

Toxicity

Naloxone, a semisynthetic opioid antagonist, is indicated for the complete or partial reversal of life-threatening CNS/respiratory depression induced by opioids. Depending on the dose, naloxone administration to a physically dependent patient on opioids will cause an abrupt return of pain and can precipitate abstinence (withdrawal) syndrome, with symptoms ranging from mild anxiety, irritability and muscle aches to life-threatening tachycardia and hypertension.[12] Newer peripherally acting opioid antagonists, methylnaltrexone and naloxegol antagonize peripheral mu opioid receptors and are used to treat refractory opioid-induced constipation.[13]

Enhancing Healthcare Team Outcomes

Opioid calculation and conversion steps

  1. Determine the total daily dose of the present opioid
  2. Calculate the 24-hour OME: Add all scheduled and breakthrough opioid doses over 24 hours. Using the equianalgesic dose chart, determine the morphine equivalents of the current opioid. This will be the 24-hour equivalent of morphine. (24-hour OME = 24-hour dose of current opioid X 30 /Number of equianalgesic units in current opioid
  3. Determine new opioid and route of administration: Using the equianalgesic dose chart, determine the 24-hour dosage of new opioid. (24-hour dose of new opioid = Total OME X Equianalgesic units of new opioid / 30)
  4. Decrease dose of new opioid due to incomplete cross-tolerance: Decrease dose of the new opioid by 50% to reach the final amount of the drug to be given
  5. Develop a pain prescription

The following are some examples. 

Case Example 1: Changing route, same opioid

Ms. T is a patient with lung cancer and painful bony metastases who is taking extended-release Morphine 90 mg every twelve hours and has tolerated it well. She is admitted to the hospital for a planned stabilization procedure of lytic bony metastasis. She is likely to suffer from uncontrolled pain if she doesn’t take her scheduled Morphine doses.

  1. Determine total daily dose of current opioid: morphine 90 mg every twelve hours 90 +90 = 180 mg
  2. Calculate the 24-hour OME: 180 mg OME per 24 hours
  3. Determine new opioid and route of administration: Patient is NPO for surgery, and her oral morphine requirement is replaceable by a continuous infusion of morphine (24-hour dose of the new opioid = 180 X 10 / 30 = 60 mg)
  4. Decrease dose of new opioid due to incomplete cross-tolerance: Since the new drug is unchanged, tolerance to the new formulation of the same drug will be the same. One does not need to decrease the dose.
  5. Develop pain prescription: A continuous infusion of morphine IV would be 60 / 24 = 2.5 mg per hour. In clinical practice, an IV infusion of an opioid frequently allows patients to deliver an additional dose during episodes of pain escalation. The prescription would more likely be for a continuous infusion of 2 mg per hour with a patient capability of 0.5 mg or 1 mg every few minutes (typically 10-15 minutes). This is called a Patient-Controlled Analgesia (PCA).

Case Example 2: Rotating opioid, keeping the same route

During her hospital stay, Ms. T develops acute renal failure from IV contrast during a procedure. To avoid toxicity from morphine in the setting of renal failure, you decide to switch her to an opioid that can be administered safely in cases of renal insufficiency, such as fentanyl or hydromorphone. On bedside assessment, her pain is well controlled, and she is receiving morphine IV continuous infusion at 2.5 mg per hour.

  1. Determine total daily dose of current opioid: (2.5 mg IV morphine per hour = 60 mg per 24 hours)
  2. Calculate the 24-hour OME: 24-hour OME = 24-hour dose of current opioid X 30 /Number of equianalgesic units in current opioid. (24-hour OME for this patient is: 60 x 30 / 10 = 180 mg)
  3. Determine new opioid and route of administration: Unlike morphine, IV hydromorphone has a short half-life and lacks clinically relevant metabolites, and is considered safer for patients with renal insufficiency. Total OME X Equianalgesic units of the new opioid / 30 = 24-hour dose of new opioid. (180 X 1.5 / 30 = 9 mg per 24 hours or 0.375 mg per hour)
  4. Decrease dose of the new opioid due to incomplete cross-tolerance: While the patient is tolerant to morphine, her tolerance to hydromorphone is likely to be incomplete. Her hydromorphone dose will need to be decreased by 50% which would be 0.1875 mg per hour.
  5. Develop pain prescription: A close approximation to a measurable dose of IV hydromorphone to the amount calculated above is 0.2 mg per hour. Similar to the solution above, the IV infusion of hydromorphone will allow an additional dose during episodes of pain escalation. The prescription would more likely be for a continuous infusion of 0.2mg per hour with a patient capability of 0.2mg every 10-15 minutes.  

Case Example 3: Change opioid and route

Towards the end of her hospital stay, Ms. T reports that her pain has been controlled with the IV hydromorphone; however, her renal function has not completely recovered, and she needs to be switched to oral opioids that are safe to use in renal dysfunction. 

  1. Determine total daily dose of current opioid: 0.2 mg IV hydromorphone per hour = 4.8 mg per 24 hours
  2. Calculate the 24-hour OME: 24-hour OME = 24-hour dose of current opioid X 30 /Number of equianalgesic units in current opioid (24-hour OME for this patient is: 4.8 x 30 / 1.5 = 96 mg)
  3. Determine new opioid and route of administration: Hydromorphone is available in a short-acting oral formulation and a 24-hour dose of oral hydromorphone calculated from the previous steps could be dosed in equal divided doses 4 hours apart. Total OME X Equianalgesic units of the new opioid / 30 = 24-hour dose of the new opioid (96 X 7.5 / 30 = 24 mg).  There is a strong likelihood however that multiple daily doses of the drug will decrease compliance and lead to poorly controlled pain. A different opioid which is long-acting and safely dosed in patients with renal insufficiency is fentanyl. Fentanyl is delivered transdermally as a patch in its long-acting formulation. A fentanyl patch takes 12-24 hours to achieve full effect. Studies clarifying equianalgesic dosing of fentanyl are lacking. To calculate a comparable dose of fentanyl a conversion formula is used. While there are several conversion formulas available, we recommend the use of the following: Fentanyl Transdermal Patch Dose calculation: The 24-hour OME divided by 2 is equal to fentanyl dose in mcg per hour  (96 / 2= 48 mcg per hour)
  4. Decrease dose of the new opioid due to incomplete cross-tolerance: Decreasing the dose of fentanyl by 50% would yield a dose of 24 mcg per hour. The closest approximation of commercially available formulations of fentanyl patch to that calculation is 25 mcg per hour.
  5. Develop pain prescription: Fentanyl patch is placed on the skin for 72 hours, after which the old patch is removed and replaced with a new one. For patients who are prescribed a long-acting opioid, it is preferable to add a short-acting opioid. The short-acting opioid helps to address breakthrough pain which is not addressed by the long-acting opioid alone. The dose of the short-acting opioid is determined as follows: Calculate 24-hour OME from long-acting opioid dose. In the example above it is: (24-hour OME = fentanyl patch dose X 2 = 50 mg) Dose of short-acting opioid is 10% of OME: Morphine 5 mg PO. A short-acting medication is usually dosed every 3-4 hours which the patient takes on an as-needed basis. Equivalent doses of different short-acting formulations of hydromorphone and oxycodone are calculated using the same principles of equianalgesia as outlined above.

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    Contributed by Mamta Bhatnagar MD, MS
Attributed To: Contributed by Mamta Bhatnagar MD, MS

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Opioid Equivalency - Questions

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What is the equivalent extended release oral morphine dose for oxycodone 5 mg, 2 tablets every 4 hours dosed around the clock?



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A 55-year-old male with metastatic lung cancer is admitted with uncontrolled pain. The workup reveals a tumor invading his rib. He has been taking hydrocodone/acetaminophen at home. Since admission, he has been prescribed IV hydromorphone 1 mg every 2 hours as needed. He has needed eight doses/24 hours. His pain is now better controlled. What was his opioid requirement in oral morphine equivalents (OME) in the last 24 hours?



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You are admitting a 75-year-old man with increasing pain because of mesothelioma and increasing pleural lesions. He has been taking oxycodone controlled-release 30 mg every 12 hours and oxycodone 5 mg every 4 hours as needed for breakthrough pain (four doses a day). He rates his pain as 7/10, and he has been tolerating the opioids well. You calculate his total oral morphine equivalents (OME) to be 120 mg in 24 hours. Given his pain is not controlled, you decide to increase his daily OMEs to 180 mg. What is your new prescription for his long-acting and short-acting opioid?



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You are asked to see a post-surgical patient for pain. He is a 63-year-old male who has pancreatic cancer. He was admitted for management of malignant small bowel obstruction and underwent a venting gastrostomy. He reports that his pain control is fair as long as he gets his medications on time. In the last 24 hours, he has received eight doses of hydrocodone/acetaminophen 5/500, four doses of morphine IV 2 mg, and two doses of hydromorphone IV 0.5 mg. What is his total oral morphine equivalents (OME) for the last 24 hours?



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A patient is taking long-acting morphine sulfate 60 mg twice daily with oxycodone 10 mg by mouth every 4 hours as needed for breakthrough pain. He presents with renal failure. You decide to switch him to a fentanyl patch because fentanyl is safer in the setting of renal dysfunction. During the history, he reports that he takes two doses of breakthrough oxycodone daily, and his pain is well controlled. The patient’s total oral morphine equivalents (OME) is 150 mg. After controlling for incomplete cross-tolerance, what is the fentanyl patch dose?



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A patient is brought to the emergency department (ED) with severe abdominal pain. His medical history is notable for metastatic rectal cancer status post diverting colostomy with chronic abdominal pain attributed to abdominal tumors. His pain had been well controlled with hydromorphone 4 mg orally as needed at home until he was unable to eat or drink and then could not take the pills. An abdominal x-ray completed in the ED reveals a large amount of stool in the colon. The patient is started on an aggressive IV laxative regimen and antiemetics. IV hydromorphone is ordered because the patient cannot take oral medications at this time. What dose of IV hydromorphone would be equivalent to the patient’s oral hydromorphone dose?



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Opioid Equivalency - References

References

Smith HS, Opioid metabolism. Mayo Clinic proceedings. 2009 Jul     [PubMed]
Davies G,Kingswood C,Street M, Pharmacokinetics of opioids in renal dysfunction. Clinical pharmacokinetics. 1996 Dec     [PubMed]
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Tuteja AK,Biskupiak J,Stoddard GJ,Lipman AG, Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 2010 Apr     [PubMed]
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Mercadante S, Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain. 1998 Jan     [PubMed]
Meuser T,Pietruck C,Radbruch L,Stute P,Lehmann KA,Grond S, Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain. 2001 Sep     [PubMed]
Bruera E,Miller MJ,Macmillan K,Kuehn N, Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain. 1992 Feb     [PubMed]
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Choi YS,Billings JA, Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. Journal of pain and symptom management. 2002 Jul     [PubMed]

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