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Opioids and Pain Management: Allergies, Conversions, Dysphagia, Oh My!

November 7, 2019

This document is for informational and educational purposes only and is not a substitute for medical advice, diagnosis, or treatment provided by a qualified health care provider.  All information contained in this document is protected by copyright and remains the property of ProCare HospiceCare.  All rights reserved.


Pain is one of the most common symptoms we encounter as hospice clinicians, but it is also the most difficult to treat, particularly with opioid allergies, complex opioid conversions, and declining ability to swallow.


Opioid Allergies

There are three different allergy subtypes, ranging from common adverse effects to true allergies, which are rare occurrences. Adverse effects are the most common and are defined as predictable effects based on the medication’s mechanism of action (e.g. nausea/vomiting, constipation, or drowsiness). Pseudo-allergies are unpredictable hypersensitivity reactions that occur after the first dose of an opioid and can range from itching to hives. True allergies are immune-mediated hypersensitivity reactions that occur after prior exposure or repeat dosing. Examples of severe true allergic reactions include: angioedema (swelling of the face, lips, and tongue), maculopapular rash, hypotension, and shock. Be sure to document the reaction type whenever possible for a complete allergy record and to ensure the safety of your patients upon switching to another opioid. There are five different chemical classes of opioids, and each class has a distinct chemical structure (Table 1). What this means is that even with a true allergy to one class of opioids, there should still be several options in another class to treat the patient’s pain.


Table 1 depicts the parent opioid in each class with its derivatives. If a patient has an allergic reaction to the parent drug, it’s likely that they may have that exact same reaction to a derivative.

*Decreased cross-tolerability within class


Conversions

It’s important to keep in mind that there isn’t a set formula for opioid conversions that works every time. Each calculation should be based on the individual patient, the amount of medications they are taking, pertinent history, and their goals for pain management. Consider following the steps below for a straightforward opioid conversion:

Step One: Convert all daily opioid usage from scheduled and PRN orders over to Oral Morphine Equivalents (OME).

Step Two: Use your hospice’s approved opioid conversion chart to convert between opioids.

(Example: Morphine to Hydromorphone; Tramadol to Oxycodone IR).

Please note that conversion to Fentanyl patches or Methadone requires use of medication-specific conversion charts.

Step Three: Reduce the final number by 25-33% to account for incomplete cross-tolerance.

Step Four: Double check your calculations, and when in doubt, call your friendly PHC pharmacist for help. Depending on the patient’s pain level and available dosage forms, you may round up or down.


Dysphagia

As patients approach end-of-life, up to 70% of patients require a non-oral route (NPO) for opioid administration. The non-oral routes that have the most supporting data are intravenous, subcutaneous, transdermal patches, and the enteral route. Routes with mixed supporting data are sublingual, buccal, rectal, and topical administration. Sublingual and rectal routes are used frequently in our patient population for convenience; however, absorption can be highly variable, depending on the medication used. The routes with the least supporting data are intramuscular injections, intravaginal, and intranasal.


Table 2 lists the various non-oral routes of administration, with examples of opioids that can be given via the route and the onset of action.

Pain management is complicated for our hospice and palliative care patients. As hospice clinicians, it’s imperative to ensure we anticipate a patient’s pain, double check conversion calculations, understand the nuances of opioid allergies, and pick the proper route of administration for maximum efficacy. This is truly the recipe for success, comfortable patients, and happy caregivers.

 

 Written by: Meri Madison, Pharm.D.



References:

  1. Fudin J. Opioid Allergy, Pseudo-allergy, or Adverse Effect? US Pharm. 2018;3. Available Online from : https://www.pharmacytimes.com/contributor/jeffrey-fudin/2018/03/opioid-allergy-pseudo-allergy-or-adverse-effect.
  2. Fudin J. Chemical Classes of Opioids. Pain Dr. http://paindr.com/wp-content/uploads/2018/02/Opioid-Structural-Classes-Figure_-updated-2018-02.pdf. Updated February 8, 2018.
  3. Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003;8:149-154.
  4. Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol. 2003 Sep-Oct;1(3):216-20.
  5. Morley JS, Bridson J, Nash TP, et al. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Palliat Med. 2003;17:576-587.
  6. Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P, Gebbia V, Ripamonti C. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001 Jun 1;19(11):2898-904.
  7. Kestenbaum MG. et al. Alternative Routes to Oral Opioid Administration in Palliative Care: A Review and Clinical Summary. Pain Medicine 2014; 15: 1129–1153.
  8. Narang N and Sharma AJ. Sublingual mucosa as a route for systemic drug delivery. International Journal of Pharmacy and Pharmaceutical Sciences 2011. 3(Supply2); 15-22.
  9. Chang A et al. Transmucosal Immediate-Release Fentanyl for Breakthrough Cancer Pain: Opportunities and Challenges for Use in Palliative Care, Journal of Pain & Palliative Care Pharmacotherapy, 2015. 29:3, 247-260.
  10.  Latuga NM et al. (2018) A Cost and Quality Analysis of Utilizing a Rectal Catheter for Medication Administration in End-of-Life Symptom Management, Journal of Pain & Palliative Care Pharmacotherapy, 32:2-3, 63-70.
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Renal impairment is relatively common in both the elderly and hospice patients, and it can affect the way medications act in the body in several ways. Most commonly, it results in decreased clearance of renally-excreted medications, leading to accumulation of the drug and/or its metabolites and subsequent adverse or toxic effects. The absorption of oral medications may be reduced in patients with renal impairment due to increased gastric pH and gut wall edema. Uremia caused by renal impairment can increase sensitivity to medications that act on the central nervous system (CNS), as well as increase the risk of hyperkalemia due to potassium-sparing drugs. In addition, uremia can enhance the potential for NSAID-induced edema or GI bleeding. Renal impairment can also lead to edema or ascites, cachexia, dehydration, decreased albumin levels and binding capacity, and decreased tissue binding, all of which can impact the effects of medications. To compensate for these renal impairment-induced changes in drug disposition, the typical actions taken regarding medication administration are to decrease the dose, increase the dosing interval, or a combination of the two. The action that would be recommended depends on the drug and its specific characteristics. There are many medications that require dose adjustment in renal impairment, but here we’ll be discussing just those that are most often seen in hospice. The goal is to make you aware of these common medications (and categories) that often need dose adjustment so they trigger a mental alert for possible follow-up if they are ordered for your patients with decreased renal function. Opioids: Many opioids can accumulate in renal impairment as the parent drug and/or metabolites. Tramadol has a maximum daily dose in all patients, but in patients with a creatinine clearance (CrCL) less than 30 mL/minute, this maximum dose is reduced to 200 mg per day and the dosing interval should be extended to every 12 hours. Morphine renal dose reductions start with a CrCL less than 60 mL/minute, with possible extension of the dosing interval at this point as well. It is typically recommended to start considering alternatives to morphine in patients with a CrCL less than 30 mL/minute, and to avoid it altogether in patients with a CrCL less than 15 mL/minute. At end of life, the benefits of morphine can sometimes outweigh the risks. Because the presentation of renal accumulation-based adverse effects may be delayed, morphine can be used even in severe renal impairment or renal failure when the prognosis is hours to days, or in dialysis patients when death is imminent. Typically, oxycodone and hydromorphone are considered preferred alternatives to morphine in patients with significant renal impairment, although they both have metabolites that can accumulate in renal failure. As a result, the dose of oxycodone should be reduced and the dosing interval increased in patients with a CrCL less than 60 mL/minute, and oxycodone extended-release products should usually be avoided in patients with a CrCL less than 30 mL/minute. Hydromorphone dose reduction is also recommended when CrCL is less than 60 mL/minute; further dose reduction and extension of the dosing interval is recommended for hydromorphone when CrCL is less than 30 mL/minute. Although hydrocodone and its active metabolites may accumulate in renal impairment, there are no dose reductions for hydrocodone/acetaminophen according to the manufacturer’s labeling. Hydrocodone extended-release products (Hysingla ER®, Zohydro ER®) are rarely used in hospice, but dose reductions are recommended in patients with moderate to severe renal impairment. Methadone and fentanyl patch are considered among the safest opioids in renal impairment because they do not have active metabolites. However, renal impairment can still alter how fentanyl moves in the body, so dose reduction is recommended in patients with a CrCL of 50 mL/minute or less. For methadone, dose reduction is not recommended until very severe renal impairment (CrCL less than 10 mL/minute). No dose reductions are recommended for buprenorphine at any degree of renal impairment, and it is generally considered safe in this population. NSAIDs: Examples of NSAIDs that are commonly used in hospice include ibuprofen (Advil®, Motrin®), naproxen (Aleve®), and meloxicam (Mobic®), and as mentioned previously, there are some concerns regarding the use of NSAIDs in renal impairment. According to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline, prolonged therapy with NSAIDs is not recommended if GFR is less than 60 mL/minute/1.73m² , and NSAIDs should typically be avoided in patients with a GFR less than 30 mL/minute/1.73m². As a general rule, NSAIDs should be used at the lowest effective dose for the shortest time possible in patients with renal impairment. In addition, NSAIDs should be avoided in patients with a high risk for developing acute kidney injury (e.g. volume depleted, elderly, and/or taking other nephrotoxic medications), and should be discontinued if acute kidney injury occurs during use. Antimicrobials: Many antimicrobials require dose reduction and/or extension of the dosing interval in renal impairment. Specific dosing recommendations depend on the antimicrobial in question and the type of infection being treated. When used for multiple doses, the dose of the antifungal fluconazole (Diflucan®) should be reduced in patients with a CrCL of 50 mL/minute or less. Examples of antibiotics commonly used in hospice that need dose adjustment include: sulfamethoxazole/trimethoprim (Bactrim®); fluoroquinolone antibiotics, including ciprofloxacin (Cipro®) and levofloxacin (Levaquin®); certain penicillin antibiotics, such as amoxicillin and amoxicillin/clavulanate (Augmentin®); and some cephalosporins, including cephalexin (Keflex®) and cefdinir (Omnicef®). Nitrofurantoin (Macrobid®, Macrodantin®) also has significant concerns in renal impairment. According to the manufacturer’s prescribing information, it is contraindicated in anuria, oliguria, or significant renal impairment (defined as a CrCL less than 60 mL/minute or clinically significant elevated serum creatinine). However, limited data suggest it is safe and effective for short-term use in patients with a CrCL of 30 to 60 mL/minute, although there appears to be an increased risk of pulmonary adverse events when eGFR is less than 50 mL/minute. In any case, nitrofurantoin should be avoided altogether in patients with a CrCL less than 30 mL/minute, due to the risk of pulmonary toxicity, hepatotoxicity, and peripheral neuropathy. Renal impairment can affect drug disposition in several ways, often increasing the risk of adverse and toxic effects. Whenever you have a patient with renal impairment, evaluate whether they are taking medications that may be cause for concern and require dose adjustment, and remember that hospice clinicians, pharmacists, and drug information resources can help by providing specific renal dosing recommendations. By Joelle K. Potts RPh, PharmD, BCGP REFERENCES: Aging and Kidney Disease. National Kidney Foundation. Available at: https://www.kidney.org/news/monthly/wkd_aging [accessed 8/8/2022] Aronoff GR, Bennett WM, Berns JS, Brier ME, Kasbekar N, Mueller BA, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th American College of Physicians, Philadelphia, PA; 2007. Renal Impairment. Chapter in: Palliative Care Formulary, 7th Edition (PCF7). Wilcock A, Howard P, Charlesworth S, Eds. Pharmaceutical Press, London, UK. Chapter 17, added April 2017; 715-35. Drug monographs. Lexcomp Online, Lexi-Drugs Online. Waltham, MA: UpToDate, Inc. https://online.lexi.com. O’Connor NR, Corcoran AM. End-stage renal disease: symptom management and advance care planning. Am Fam Physician. 2012; 85(7): 705-10. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements. Jan 2013; 3(1). Available at: www.kidney-international.org Macrobid® Prescribing Information. Proctor and Gamble Pharmaceuticals, Inc. Cincinnati, OH. Revised Jan 2009. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf [accessed 6/13/2022] Macrodantin® Prescribing Information. Almatica Pharma Inc. Pine Brook, NJ. Revised Mar 2013. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016620s072lbl.pdf [accessed 6/13/2022] 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated Beers Criteria® for potentially inappropriate medication use in older adults. JAGS. 2019; 00: 1-21
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