Long-Acting Opioids Pharmacologic Treatment

Fentanyl patches and methadone are also effective as long-acting agents but are generally reserved when therapy with morphine or oxyco- done has been unsuccessful or side effects have precluded their use. Equianalgesic conversions of fentanyl and methadone can be complicated and vary based on the total amount of OMEs. Methadone has unique pharmacokinetic proper- ties that must be taken into consideration due to a long half-life requiring initially frequent dosing but later only every 12–24 h dosing. Methadone is potentially benefi cial as it has less pruritus side effect and also may help treat concomitant nau- sea. A fentanyl patch can be a convenient way to provide pain medication delivery in the patient unable to easily take oral medications. Fentanyl and methadone should be prescribed by clinicians experienced in their use. Case 1 Continued Starting Long-Acting Opioids You see Eric 2 days later and he tells you the mor- phine is working well. Eric says his pain drops Table 9.3 Pain management algorithm a Pain level Rescue medication Sustained medication Step 1 Mild pain Start rescue medication: Consider sustained therapy: Start a nonopioid analgesic NSAID or acetaminophen as needed Consider a standing dose for short period of time Step 2 Moderate pain Start or escalate rescue medication: Consider sustained therapy: Acetaminophen with hydrocodone Acetaminophen with hydrocodone same dosage on scheduled basis Step 3 Severe pain Start or escalate rescue medication: Start or escalate sustained medication: Morphine oral immediate-release preparation Morphine oral immediate-release preparation a Opioid naïve: 0.2–0.3 mgkgdose q3-4 h prn a Opioid naïve: 0.2–0.3 mgkgdose q3-4 h prn b Opioid exposed: increase previous dose 25–50 for moderate pain and 50–100 for severe pain b Opioid exposed: total daily morphine dose divided every 3–4 h prn If meant for prolonged use, consider sustained-release morphine formulation Use of methadone or fentanyl patch should be in conjunction with palliative care or pain specialist Step 4 Severe- persistent pain Start or increase rescue medication: Initiate or escalate sustained medication: Morphine: IV, SC a Opioid naïve 6 months: 0.05–0.1 mg kgdose q3-4 h prn a Transition sustained medication to IV equivalent b Consider an infusion b Opioid naïve 6 months: 0.1–0.2 mg kgdose every 3–4 h prn c Opioid exposed: previous total daily oral dose converted to IV morphine equivalent and divided by frequency Consider patient-controlled analgesia PCA with morphine: a Opioid naïve: basal infusion, 0–0.02 mg kgh; demand dose, 0.015–0.02 mgkg dose; lockout interval, 5–15 min b Opioid exposed: basal infusion, daily dose divided by 24 h; demand dose, 50–100 of hourly dose; lockout interval, 5–15 min NSAID nonsteroidal anti-infl ammatory drug, IV intravenous, SC subcutaneous Adapted from Klick and Hauer 2010 a Level of evidence 1C for all recommendations per Guyatt et al. 2006 ; see Preface S. Malhotra and S. Maurer from 8 of 10 to 3 of 10 within about 30 min of taking the medication, and the pain relief lasts for 3–4 h. His mother says he uses seven doses a day, but that he has excellent pain control. However, Eric does say that when he wakes up from sleeping his pain is really bad and takes some time to come back under control. Thus, his mother has been waking him up at night to give him the morphine. His mom is tired, but she tells you she’s willing to do whatever it takes to keep him comfortable. Plan You decide that Eric would best be served with a long-acting opioid. To start, you calculate his total daily opioid requirement. 7 5 7 52 5 . . mg po morphine doses day mg po morphine per day × = You then determine that about 23 of his daily dose should be in his long-acting medication. Taking 23 of 52.5 mg, you decide that approxi- mately 35 mg of morphine per day should be given in a long-acting form. Since morphine has worked so well for him, you choose sustained- release morphine as your long-acting agent. Noting that it comes in 15 mg tablets, you pre- scribe 15 mg by mouth twice a day, which will provide 30 mg per day in a long-acting form. You take care to advise Eric and his mother that this should be taken roughly every 12 h regardless of his pain level and that this medication will not help with breakthrough pain. He will also need a breakthrough dose; instructions for this calcula- tion are in Sect. 9.4.4 .

9.4.4 Breakthrough Dosing

Breakthrough dosing of pain medications should be used for acute pain that is not controlled by a long-acting medication. When possible, the same opioid should be used as the short- and long- acting agent. This dose should be calculated as 10–20 of the total daily long-acting dose every 3–4 h as needed. All patients should have access to a breakthrough medication. An adult study demonstrated that up to 67 of cancer patients with well-controlled pain have transitory episodes of breakthrough pain requiring treatment Bruera and Neumann 1999 . Younger children with can- cer tend to experience more breakthrough pain than older children Friedrichsdorf et al. 2007 . If more than three breakthrough doses are needed in 24 h, consideration should be given to increasing the long-acting opioid dose. This should be done by calculating the daily OME from the long-acting opioid and from the total amount of breakthrough medicine required. A new long-acting dose can then be calculated using the principles listed in Sect. 9.4.3 . A new, higher, breakthrough dose should be calculated as 10–20 of the new, total daily long- acting dose. Case 2 Calculating Breakthrough Dosing You are taking care of a 50 kg girl with osteosar- coma of the proximal tibia. She is now 6 days post gross total resection of her tumor with a limb-spar- ing procedure. She has been on morphine by patient-controlled analgesia PCA, and from a surgical standpoint, she is ready for discharge. Her morphine PCA settings have been a continuous rate of 1 mgh with a demand dose of 1.5 mg every 15 min. She has been receiving about eight demand doses per day for the past 2 days and notes good pain control. The surgical team is asking you to determine an outpatient pain plan. She requests that you attempt to keep things in pill form. Plan The fi rst step is to determine the total daily mor- phine requirement. Each day she receives 24 mg 1 mgh from her continuous rate and 12 mg 1.5 mg × 8 doses from her demand, giving a total dose of 36 mg of IV morphineday. Next you must decide on the oral formulation. Since morphine has worked well for her, you decide that you will use sustained-release morphine as your long-acting agent and immediate-release morphine for breakthrough. To calculate the proper dose, you then need to convert the medication into OMEs Table 9.2 , see Sect. 9.4.5 : 36 30 10 108 mg IV morphine mg PO morphine mg IV morphine mg PO morphin × = ee The next step is to determine the amount of medi- cation to place in long-acting form. In general, you would choose to take 23 of the total daily dose. Thus, 23 of 108 mg PO morphine is about 72 mg PO morphine. Noting that sustained- release morphine comes in 30 mg tablets given every 12 h, you decide to use 30 mg twice daily as the long-acting dose. Next you need to calculate the breakthrough dose. Knowing that you are now going to give 60 mg per day as a long-acting dose, you can estimate the breakthrough dose at 10–20 of the long-acting dose. This gives you a dose some- where between 6 and 12 mg of immediate-release morphine. Recognizing that immediate-release morphine comes in 15 mg tablets, you choose a breakthrough dose of 7.5 mg. Hence, you have settled on the following plan: 1. Sustained-release morphine 30 mg PO twice a day 2. Immediate-release morphine 7.5 mg PO every 3 h as needed for breakthrough pain

9.4.5 Opioid Rotation

and Equianalgesia When titrating or changing opiates, it is impor- tant to start by calculating the previous day’s OME. All opioids produce analgesia by the same mechanism; thus, if provided in equianalgesic doses, they will produce the same degree of anal- gesia Table 9.2 . The most common reasons to change from one opioid to another are side effects and poor response to pain control despite appro- priate titration Drake et al. 2004 . Other indica- tions for opioid rotation include renal failure, problematic drug-drug interactions, preference or need for different route of administration or fi nancial considerations. When rotating opioids it is important to con- sider incomplete cross-tolerance. This concept takes into account that tolerance developed to one opioid does not imply complete tolerance to another. Also, the new drug may be more effec- tive due to differences in drug bioavailability or potency Pasero and McCaffery 2011 . To account for this phenomenon, a dose reduction by 25–50 should occur when rotating opioids Indelicato and Portenoy 2002 . In most cases a 25 reduction is appropriate but practitioners should use clinical judgment in determining how much of a dose reduction should occur as a result of incomplete cross- tolerance. For example, in the case of a patient who has undergone rapid increases in opioid dosing for pain subsequently deemed to be allodynia, a dose reduction of 50 may be more appropriate. Case 3 Opioid Switching You are taking care of a 50 kg young man with newly diagnosed leukemia. He’s been using mor- phine 5 mg IV every 3 h as needed for bone pain. Although he notes good pain relief, he has been itching uncontrollably. He asks you if there is anything you can do to help with his pain but keep him from itching. Plan This is one of the most common reasons to switch opioids. Although you could try a medication to treat the itching, changing the offending agent avoids polypharmacy. You decide that hydromor- phone would be a nice alternative. To calculate a dose, you fi rst need to determine the equianalge- sic dose of hydromorphone and morphine Table 9.2 : 5 1 5 10 0 75 mg IV morphine mg IV hydromorphone mg IV morphine mg IV h × = . . y ydromorphone The last step is to account for incomplete cross- tolerance. A dose reduction of 25 would provide a dose of about 0.56 mg of IV hydro- morphone. Thus, an order for 0.6 mg of IV hydromorphone every 3 h as needed for pain would be appropriate.

9.4.6 Patient-Controlled Analgesia

Calculations Patient-controlled analgesia PCA is indicated for use when pain is not controlled with oral medications, there is inability to take oral medi-