Side effects and toxicity of analgesics Disclaimer: This presentation contains information on the general principles of pain management. This presentation cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician, or health care provider, to determine the best course of treatment for the patient. Treat the Pain and its partners assume no responsibility for any injury or damage to persons or property arising out of or related to any use of these materials, or for any errors or omissions. Last updated on January 12, 2015

Objectives Discuss side effects of Step 1, Step 2, and Step 3 analgesics Review signs of opioid toxicity Describe treatment options of opioid toxicity 2

Step 1 analgesics: paracetamol Hepatotoxicity can occur if more than the maximum dose (4g) is given per day Alcohol-dependent and undernourished patients are at a higher risk Contraindications: Severe hepatic and renal impairment, alcohol dependence, undernourishment, and glucose-6-phosphate dehydrogenase deficiency Beating Pain, 2 nd Ed. APCA (2012); Guide to Pain Management in Low-Resource Settings, IASP (2010)3

Step 1 analgesics: NSAIDs Side effects are usually seen with longer-term use (>7 days) Gastro-intestinal (GI) bleeding – If any GI symptoms develop (dypepsia, epigastric pain), stop and give H2 receptor antagonist, e.g. Ranitidine Renal failure Contraindications Gastrointestinal ulceration, hemophilia, hypersensitivity to aspirin, thrombocytopenia, young children, pregnancy (especially third trimester), breastfeeding, and advanced renal impairment Beating Pain, 2 nd Ed. APCA (2012); Guide to Pain Management in Low-Resource Settings, IASP (2010)4

Step 2 analgesics: weak opioids Weak opioids are considered very safe, even in patients with impaired organ function Codeine – Give laxatives to avoid constipation unless patient has diarrhoea Tramadol – Use with caution in epileptic patients, especially if patient is on other drugs that lower the seizure threshold – May cause serotonin syndrome in patients on other serotonergic medications Beating Pain, 2 nd Ed. APCA (2012); Guide to Pain Management in Low-Resource Settings, IASP (2010)5

Step 3 analgesic: morphine When used correctly, problems like dependency, addiction, tolerance, and respiratory depression are rare Opioids are not toxic to any organ – No contraindications except history of allergic reactions (rare) Beating Pain, 2 nd Ed. APCA (2012); Guide to Pain Management in Low-Resource Settings, IASP (2010) 6

Step 3 analgesic: morphine Constipation is a very common side effect of all opioids and does not resolve spontaneously Laxatives should be prescribed as prophylaxis unless patient has diarrhoea Treat with a stimulant laxative – i.e. Bisacodyl 5mg at night, increasing to 15mg if needed Beating Pain, 2 nd Ed. APCA (2012)7

Step 3 analgesic: morphine Nausea and vomiting Usually mild and resolves within one week Anti-emetics (metoclopramide or haloperidol) can be given for the first few days of treatment – Metoclopromide 10mg every 8 hours or haloperidol 1.5mg once a day Itching Less common Treat with chlorpheniramine Beating Pain, 2 nd Ed. APCA (2012), Guide to Pain Management in Low-Resource Settings, IASP (2010) 8

Step 3 analgesic: morphine Drowsiness Usually resolves within one week Advise patients not to perform dangerous tasks or operate heavy machinery for 2 weeks while they adjust to the medications Patients who have been unable to sleep well due to pain may initially sleep for long periods once their pain has been relieved – These patients should be easily arousable If it does not improve, reduce the morphine dose Beating Pain, 2 nd Ed. APCA (2012)9

Step 3 analgesic: morphine Hepatic and renal impairment Not a contraindication for use Titrate slowly and carefully to avoid accumulation of medication or active metabolites – Consider increasing interval between doses to 6, 8, or even 12 hours Elderly Older people respond well to lower doses Consider reducing the dose or increasing the dosing interval to minimize side effects Beating Pain, 2 nd Ed. APCA (2012); Guide to Pain Management in Low-Resource Settings, IASP (2010) 10

Opioid toxicity Toxic effects of opioids are rare when they are used in appropriate doses Signs include – Drowsiness that does not improve – Confusion – Hallucinations – Myoclonus (abrupt spasms or muscle twitching) – Respiratory depression (slow breathing) – Pinpoint pupils Beating Pain, 2 nd Ed. APCA (2012)11

Opioid toxicity If you are concerned that a patient is experiencing toxicity, reduce the dose by 50% and consider giving parenteral fluids to increase excretion In severe cases, stop the opioid and give Naloxone, an opioid antagonist – Naloxone is rarely used and should be used with caution as it will precipitate pain crisis Haloperidol 1.5-5mg at night may help with any hallucinations or confusion – Be sure to rule out other causes (such as urinary tract infection, hypoxia, or side effect of another medication) Beating Pain, 2 nd Ed. APCA (2012), Dr. Kathleen Doyle12

Take home messages The use of opioids can cause side effects; with proper use these side effects can be mediated When using opioids, give laxatives to avoid constipation unless patient has diarrhoea When used correctly, patients don’t become dependent or addicted to morphine Opioids are not toxic to any organ 13

References African Palliative Care Association. Beating Pain: a pocketguide for pain management in Africa, 2nd Ed. [Internet] Available from: African Palliative Care Association. Using opioids to manage pain: a pocket guide for health professionals in Africa [Internet] Available from: Amery J, editor. Children’s Palliative Care in Africa [Internet] Available from: Africa-Full-Text.pdf Kopf A, Patel N, editors. Guide to Pain Management in Low-Resource Settings [Internet] Available from: pain.org/files/Content/ContentFolders/Publications2/FreeBooks/Guide_to_Pain_ Management_in_Low-Resource_Settings.pdf The Palliative Care Association of Uganda and the Uganda Ministry of Health. Introductory Palliative Care Course for Healthcare Professionals