WHO Analgesic Ladder 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.

Objectives Review the World Health Organization (WHO) analgesic ladder Discuss treatment for mild, moderate, or severe pain Review additional treatment principles when using opioids

Background The WHO analgesic ladder was introduced in 1986 3-step ladder for adults Updated in 2012 to include 2-step ladder for children Framework for pharmacological management of pain 80-90% of patients are effectively treated using the WHO 3-step approach http://www.who.int/cancer/palliative/painladder/en/

WHO Analgesic Ladder: adults Step 3 Strong opioid Step 2 Weak opioid Step up if pain persists or increases Severe pain Step up if pain persists or increases Step 1 Non-opioid Moderate pain +/- non-opioid +/- adjuvant Mild pain +/- non-opioid +/- adjuvant +/- adjuvant Consider prophylactic laxatives to avoid constipation Non-opioids ibuprofen or other NSAID, paracetamol (acetaminophen), or aspirin Weak opioids codeine, tramadol, or low-dose morphine Strong opioids morphine, fentanyl, oxycodone, hydromorphone, buprenorphine Adjuvants antidepressant, anticonvulsant, antispasmodic, muscle relaxant, bisphosphonate, or corticosteroid Combining an opioid and non-opioid is effective, but do not combine drugs of the same class. Time doses based on drug half-life (“dose by the clock”); do not wait for pain to recur 4 Adapted by Treat the Pain from World Health Organization http://www.who.int/cancer/palliative/painladder/en/ (accessed 7 November 2013)

Using the WHO ladder for adults Mild pain - start with a non-opioid, for example with regular paracetamol or non- steroidal anti-inflammatory drug (NSAID), then move up steps if pain remains uncontrolled Moderate - start with a weak opioid, for example, codeine or low-dose morphine Severe - start with a strong opioid, for example, morphine, to control pain early Adjuvants can be used at any step Beating Pain, 2nd Ed. APCA (2012)

Step 1 – mild pain: non-opioids Paracetamol Adult dose: 500mg-1g by mouth every 6 hours; maximum daily dose 4g Note: Hepatoxicity can occur if more than the maximum dose is given per day Patients with liver impairment should use lower amounts or avoid use altogether Paracetamol can be combined with an NSAID Beating Pain, 2nd Ed. APCA (2012)

Step 1 – mild pain: non-opioids Ibuprofen (NSAID) Adult dose: 400mg by mouth every 6-8 hours; maximum daily dose 1.2g Give with food and avoid in asthmatic patients Beating Pain, 2nd Ed. APCA (2012)

Step 1 – mild pain: non-opioids Diclofenac (NSAID) Adult dose: 50mg by mouth every 8 hours; maximum daily dose 150mg Give with food and avoid in asthmatic patients Beating Pain, 2nd Ed. APCA (2012)

Cautions with NSAIDs NSAIDs can cause serious side effects, particularly after using for more than 7-10 days Gastro-intestinal (GI) bleeding or renal toxicity If GI symptoms occur, stop and give H2 receptor antagonist. e.g. Ranitidine Not for use in patients with renal impairment Beating Pain, 2nd Ed. APCA (2012)

Step 2 – moderate pain: weak opioids Tramadol Adult dose: 50-100mg by mouth every 4-6 hours Start with a regular dose and increase if no response (dose limit: 400mg/day) Use with caution in epileptic cases, especially if patient is taking other drugs that lower the seizure threshold May cause serotonin syndrome in patients on other serotonergic medications Beating Pain, 2nd Ed. APCA (2012)

Step 2 – moderate pain: weak opioids Codeine Adult dose: 30-60mg by mouth every 4 hours; maximum daily dose 240mg If pain relief is not achieved with 240mg/day, move to strong opioid Can be combined with Step 1 analgesic Give laxative to avoid constipation unless patient has diarrhoea Genetic variability can lead to variable rates of metabolism which may make codeine ineffective or lead to excessive side effects Beating Pain, 2nd Ed. APCA (2012)

Step 2 – moderate pain: weak opioids Low-dose morphine Some palliative care experts recommend using low-dose morphine in step 2 because it is associated with fewer side effects compared to other weak opioids Beating Pain, 2nd Ed. APCA (2012)

Step 3 – severe pain: strong opioids Morphine “Gold standard” against which other opioid analgesics are measured When used correctly, patients don’t become dependent or addicted, tolerance is uncommon, and respiratory depression doesn’t usually occur Beating Pain, 2nd Ed. APCA (2012)

Step 3 – severe pain: strong opioids Less commonly used strong opioids (covered in separate lecture) Fentanyl Oxycodone Hydromorphone Methadone Beating Pain, 2nd Ed. APCA (2012)

Step 3 – severe pain: strong opioids Morphine Adult starting dose: 2.5–20mg by mouth every 4 hours depending on age, previous use of opiates, etc. Patients changing from regular administration of a Step 2 opioid: 10mg by mouth every 4 hours If the patient has experienced weight loss from sickness or has not progressed onto Step 2 analgesics: 5mg by mouth every 4 hours Frail or elderly patients: 2.5mg by mouth every 6 to 8 hours due to the likelihood of impaired renal function Beating Pain, 2nd Ed. APCA (2012)

Step 3 – severe pain: strong opioids Morphine is available as immediate-release or sustained-release formulations Immediate-release Dose every 4 hours Use to titrate starting dose and treat breakthrough pain Beating Pain, 2nd Ed. APCA (2012).

Step 3 – severe pain: strong opioids Sustained-release (or slow-release) Dose every 8-24 hours, depending on the formulation After determining daily dose with immediate-release morphine, can change to sustained-release morphine, being careful to adjust dose as needed to maintain the total daily dose Priority should be given to making immediate-release formulations available Beating Pain, 2nd Ed. APCA (2012).

Step 3 – severe pain: strong opioids Morphine Increase dose gradually until pain is controlled The correct morphine dose is the one that gives pain relief without side effects: there is no ‘ceiling’ or maximum dose Beating Pain, 2nd Ed. APCA (2012)

Caution: pethidine Pethidine is not suitable for patients with chronic pain It has a faster onset of action and a shorter duration of action than morphine and needs more frequent dosing: every 2–3 hours Pethidine is metabolised to norpethidine which has side effects inducing central nervous system excitability including mood changes, tremors, myoclonus (sudden jerking of the limbs) and convulsions Pethidine was removed from the WHO essential medicines list in 2003 because it was judged to be inferior to morphine due to its toxicity on the central nervous system and is generally more expensive than morphine Beating Pain, 2nd Ed. APCA (2012); The Selection and Use of Essential Medicines – WHO Technical Report Series, No. 920. 2003.

Treatment principles By the mouth: Use the oral route whenever possible By the clock: Administer analgesics according to regular schedule based on duration of effectiveness rather than “as needed”, except when titrating dose By the ladder: Use the WHO analgesic ladder. If after giving the optimum dose an analgesic does not control pain, move up the ladder; do not move sideways in the same level By the patient: The right dose is the one that relieves pain. Titrate the dose upwards until pain is relieved or side effects prevent moving up further Beating Pain, 2nd Ed. APCA (2012)

Stopping or changing opioids When stopping an opioid, reduce daily dose by 25% each day to avoid symptoms of withdrawal When changing from one opioid to another, be mindful of the need to convert doses Check reference materials or consult an expert Oxford Textbook of Palliative Medicine (2010)

Key treatment principle: prophylactic laxatives All patients on opioids are at high risk for constipation, and laxatives should be ordered unless contraindicated Beating Pain, 2nd Ed. APCA (2012)

Take home message The WHO ladder, an important tool of managing pain, can effectively treat 80-90% of the patients at this facility For non-responsive pain, please refer to a pain specialist

Practical Assessment Esther, a 28 year-old woman with cancer, reports a pain score of 5 out of 10. Which medicines would you consider prescribing? A. Codeine B. Tramadol C. Low-dose morphine D. Any of the above If you prescribe low-dose morphine, what is Esther’s starting dose? 2.5mg every four hours What other prescriptions must be written at the same time? Laxatives

References African Palliative Care Association. Beating Pain: a pocketguide for pain management in Africa, 2nd Ed. [Internet]. 2012. Available from: http://www.africanpalliativecare.org/images/stories/pdf/beating_pain.pdf African Palliative Care Association. Using opioids to manage pain: a pocket guide for health professionals in Africa [Internet]. 2010. Available from: http://www.africanpalliativecare.org/images/stories/pdf/using_opiods.pdf Amery J, editor. Children’s Palliative Care in Africa [Internet]. 2009. Available from: http://www.icpcn.org/wp-content/uploads/2013/08/Childrens-Palliative-Care-in- Africa-Full-Text.pdf Kopf A, Patel N, editors. Guide to Pain Management in Low-Resource Settings [Internet]. 2010. Available from: http://www.iasp- 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. 2013.