type in your name

2. Low technology treatment methods Cancer Pain type in your name Type in the nameof your institution

3. Aims and topics • General aspects concerning cancer pain • Recommendations and guidelines for the use of drugs in the management of cancer pain • Issue of opioid availability • Essential analgesic drug list • Pearls of wisdom • Case report • Reference list

4. Cancer Pain • Up to 70% of cancer patients suffer from pain. • Most patients can obtain sufficient pain relief with oral analgesics. • Use alternative methods for drugs administration (e.g. intravenous or subcutaneous) only when oral administration is not possible. • Use the Pain Relief Ladder of the World Health Organization (WHO) as a guideline for the use of drugs in the management of pain.

5. Cancer Pain • Cancer pain may include different qualities, locations and intensities depending on the type and stage of the cancer. • The dosage of drugs might require frequent changes during treatment due to progression of the tumour or to side effects. • In the case of new symptoms and pain you should always think of a reasonable alternative and symptomatic treatment.

6. Cancer Pain • Pain intensity is influenced not only by somatic findings but also by psychological factors such as fear, depression, sleeplessness • In this case you often can reduce analgesics by “treating” the psychosocial factors. • Talk about the problems with your patient and his family.

7. Case report James Window is a 59 year old policeman, suffering from prostate cancer since 2009. Following surgery, he went into remission for 2 years and continued with his work. However, he then experienced back pain and after undergoing tests, metastases were detected in his spine. He underwent radiotherapy and received ibuprofen 2 x 600mg/day, resulting in reduction of pain for about 3 months.

8. Case report (cont.) The local pain increased despite taking more ibuprofen?. As a result, James‘s physician prescribed, tramadol, a low-efficacy opioid. He was started on the lowest dosage of 2 x 50mg/day, with an extended-release formulation. After a short time, the dose was increased to 2 x 100mg and then to 2 x 150mg. At this point, the pain decreased to a tolerable level without side effects.

9. Case report (cont.) At this stage, his physician decided to change the treatment to morphine. He started with a dose of 2 x 30mg morphine using an extended-release formula and 10mg morphine with an immediate-release (IR) formula in the event of „break-through pain“. After 3 days of treatment using this regimen, the physician counted the number of IR tablets that James used (6-7 a day) and converted the dose to the extended-release formula. The dosage of morphine prescribed to Richard was then 2 x 100mg / day. w/o leaving the option for IR MO?

10. WHO Pain Relief Ladder By the clock By the mouth By the ladder By the individual Step I Step II Step III High potent opioids Low potent opioids Non-opioids Non-opioids Non-opioids

11. Combination of drugs • Often we need to combine several drugs to improve the total analgesic effect • a non-opioid with an opioid. • ibuprofen or diclofenac with paracetamol (acetaminophen) or metamizol (dipyrone) (i.e. an NSAID with a simple analgesic). • There is no improvement in the analgesia by combining metamizol with paracetamol (i.e. two simple analgesics).

12. Non-opioids • COX inhibitors inhibit peripheral and central (dorsal horn of the spinal cord) hyperalgesia by ínhibiting production of prostaglandins • Analgesic: paracetamol, metamizol • Analgesic and anti-inflammatory: ibuprofen, diclofenac • Selective COX inhibitors: celecoxib, etoricoxib

13. Possible side-effects • Overdose of acetaminophen can lead to liver failure. • Ibuprofen and diclofenac can produce gastrointestinal problems such as ulcers and kidney failure • Metamizol rarely provokes leukopenia and agranulozytosis (about 1:1 Mio, higher risk in Scandinavia because of genetic reasons)

14. Dosage • Paracetamol: 4 x 1000mg (daily dose < 4.0g because of possible liver toxicity) • Metamizol: 4 x 500 – 1000mg (daily dose < 6.0g) • Ibuprofen: 3 x 400-800mg (maximum daily dose 2400mg) • Diclofenac 3 x 50mg or 2 x 75mg extended release formula (maximum daily dose 150mg) • Celecoxib 2 x 100mg-2 x 200mg, Etoricoxib 1 x 60-90mg • Duration of treatment ?

15. Treatment with opioids • Opioids are the most potent of the analgesic drugs and you should use them early in cancer pain treatment • They bind to opioid receptors in the cell membranes in the central and peripheral nervous system: µ-, ĸ-, δ-receptors • Typical side effects of opioids are dose related and mostly appear at the beginning of treatment • Titrate opioids slowly to the most effective analgesic dose to reduce side effects

16. Opioid side effects • constipation, reduction of the gastrointestinal motility • nausea, vomiting, • sedation, dizziness • cognitive impairment • respiratory depression, antitussive effects • pruritus • muscle rigidity, urinary retention

17. Treatment with opioids • Don‘t be afraid of opioid dependency when treating cancer pain • addiction is exceedingly rare during long-term opioid treatment of cancer pain. • Under-treatment of pain may lead to drug-seeking behavior by the patient (=pseudo-addiction).

18. Treatment with opioids • Don‘t be afraid of respiratory depression – patients receiving long-term opioid therapy generally develop tolerance to the respiratory-depressant effects of opioids. • Side effects – except for constipation – decrease during prolonged and regular administraiton of opioids. • Opioid-induced-constipation requires that you combine a laxative in nearly all patients treated with an opioid.

19. Treatment with opioids • How to use opioids in cancer pain? • Prefer the extended-release/prolonged-release formulations of oral opioids: onset within 30 - 60 minutes, duration 8 - 12 hours • Treat breakthrough pain with immediate-release formulations: onset within 30 minutes, duration 4 - 6 hours (prescribe 1/5 of the daily opioid dose) • The combination of opioids and non-opioids helps to reduce the dosage and the side effects of the single drug

20. Weak opioid • Tramadol belongs to step II of the WHO ladder, it binds not only to opioid receptors but also to norepinephrone and serotonin reuptake inhibitors • It has 0.2 times the analgesic potency of morphine • It exists as an oral and parenteral formulation • Decrease the dosage in case of renal or hepatic impairment because of the risk of accumulation and respiratory depression

21. Strong opioids • Morphine is a strong µ-opioid agonist and belongs to step III of the WHO ladder • Commonly used as reference for all other opioids • It can be applied by all routes of administration • The active metabolites accumulate in case of renal impairment and can increase side effects • There are extended- (10, 20, 30, 60, 100, 200mg) and immediate-release (10mg, 20mg) formulations.

22. Strong opioids • Hydromorphone is also a strong µ-opioid agonist • It has about a 4 - 5 times the analgesic potency of morphine, with a 12h duration of effect • It has an oral and parenteral formulation for s.c., i.m. or i.v. application, an extended- (4mg, 8mg, 12mg 16mg 24mg capsules) and immediate-release formulations (1.3mg, 2.6mg capsules) • Has a low plasma protein binding and therefore, a possibly lower risk of interaction with other drugs

23. Strong opioids • Oxycodone: with 2 times the analgetic potency of morphine and a 8 - 12h duration • High oral bioavailability of 60-80% • It is available as an oral extended- (10mg, 20mg, 40mg, 80mg) and immediate-release formula (Oxycodone 5mg, 10mg, 20mg capsules buccal or sublingual) or Oxycodone iv 10mg, 20mg • There is a fixed formula with naloxone to reduce the risk for drug induced constipation (Targin)

24. Strong opioids • Fentanyl: has 80-100 times the analgetic potency of morphine, it is metabolized in the liver, has a rapid onset and a short duration • It mainly exists as a parenteral formula but a transdermal application (Fentanyl patches with 12, 25, 50, 75, 100µg/h, change of the patches every 72 hours) is also widely used • For breakthrough pain there are nasal buccal or transmucosal formula (100, 200, 400, 600, 800, 1200, 1600µg)

25. Routes of opioid administration • Oral, rectal • Nasal, sublingual, buccal • Transdermal as a patch • Intramuscular via intermittent injection (NOT recommended particularily when long term treatment is planned!) • Subcutaneous - intermittent injections or continuous infusion • Intravenous - intermittent injections or continuous infusion • Spinal epidural • Spinal intrathecal

26. Case report • Richard‘s disease progressed and with it the intensity of his pain and onset of a new type of pain: burning pain which did not respond to the morphine. Also he got a sensitive deficit perineal because of an infiltration of the Pudendal nerve?? • Richard‘s physician prescribed dexamethason 12 mg and gabapentine 3 x 300mg (starting with x mg and increaseing in 100mg steps). As a result, the pain decreased again.

27. Neuropathic pain • This pain results from a damage to afferent neurons and altered pain transmission and processing in the spinal cord and brain • Pain characteristics and sensations are different • Neuropathic pain can be difficult to treat, often you need more than opioids: anticonvulsants, antidepressants • Examples for neuropathic pain in cancer pain: neuropathy after chemotherapy or radiotherapy, compression of nerves by the tumor or metastases

28. How to diagnose neuropathic pain? • The patient‘s description of the pain quality: lancinating, burning, pricking, tender, numb, throbbing, nagging, hot • The pain projection and and pain radiation along a course of nerves with segmental or peripheral distribution, a glove-like distribution or attributed to a dermatome • Paresis or muscular weakness and pain in the extremities in the case of a plexopathy

29. How to diagnose neuropathic pain? • By careful neurological examination: • Look for somatosensory abnormalities such as dysaesthesias, hyperalgesia, hypaesthesia, dynamic or thermal allodynia • Look for paresis or muskular weakness and pain • For examination use a stub-point needle, a warm or cold spoon, a cottonwool tip

30. Drugs for neuropathic pain • Most commonly used anticonvulsants are gabapentin, pregabalin and carbamazepine • Most commonly used antidepressant: amitriptyline, doxepin • They act as sodium and calcium channel blockers of the neuronal cells • Because of possible side-effects of the central nervous system carefully raise the dosage: „start low, go slow“!

31. Drugs for neuropathic pain • Carbamazepine: initial dose 2 x 100mg/dayup to 2 x 800mg/day • Gabapentin: initial dose 3 x 100mg/dayup to 3 x 800mg/day • Amitriptyline/Doxepin: initial dose 1 x 25mg in the evening up to 1 x 75mg • Possible side effects: constipation, dry mouth, drowsiness, sedation, arrhythmias, induction and elevation of liver enzymes, edema

32. Drugs for neuropathic pain • Corticosteroids such as dexamethason can reduce pain due to nerve structure compression or edema of metastases • Prescribe initially 1 x 16-24mg/day in the morningor radiotherapy and taper off gradually after pain reduction • Sometimes a combination with opioids will improve pain reduction

33. Case report • James‘s pain was treated sufficiently but he experienced new symptoms: constipation and nausea. • The constipation was treated with lactulose 3 x 10mg/day and the nausea wtih metoclopramide 4 x 10mg/day • James‘s situation was stable for the next 6 months.

34. Case report • After this time pain increased again because of his progressive disease. He got a new burning pain without reduction of the pain intensity by taking more morphine. Also he got a sensitive deficit perineal because of an infiltration of the plexus pudendus. Under the treatment with dexamethasone 12 mg and gabapentin 3 x 300mg/day (going up in 100mg steps) the pain decreased again. was already in slide 24

35. Case report • Due to his cancer (and possibly a side effect of the medications??), James felt tired and lethargic. He had lost a great deal of strength and energy. Though the quality of his life was good on some days, on other days he was depressed. On the days he was depressed, the pain was more obtrusive than during the ‘good’ days. His family and friends spent time with James and paid him more attention. Consequently, until his death there was no need to increase the doses of the medications he was given.

36. Treatment of constipation • Sometimes it is harder to treat the constipation than pain. • Opioids reduce the gastrointestinal motility, decrease gastrointestinal mucus secretion, increase fluid absorption mainly by binding to peripheral opioid receptors in the mesenteric and submucous plexus and to cerebral and spinal receptors • There is no tolerance to constipation !

37. Treatment of constipation • Co-administer laxatives such as: lactulose 3 x 10mg to 3 x 40mg/day ormacrogol 1-3 sachets/day or non-resorbable oils/paraffines • Emphasize the need for a normal daily fluid intake • As long as is possible, encourage the patient to be mobile

38. Treatment of opioid induced emesis • About 20% of the patients treated with opioids suffer from emesis • First choice: metoclopramide 4 x 10mg and haloperidol 3 x 0.3-0.5mg orally, subcutaneously or intravenously • It is better to combine opioids and antiemetics at the beginning of the treatment as a prophylaxis • After 7 days of treatment, try to withhold the medication; tolerance to opioid-induced emesis typically developes after this period of time.

39. Issue of opioid availability • Many patients all over the world do not receive adequate relief of pain because of excessive regulatory restrictions on the availability and accessibility of opioids. • There is a reluctance about using opioid analgesics and fear of abuse • Another problem is the lack of knowledge regarding pain relief and opioids among professionals and the public • Ensure opioid availability!

40. Essential WHO analgesic drug list • Tramadol • Morphine, Sevredol • Hydromorphine • Oxycodone • Fentanyl • ParacetamolAcetaminophenon • Metamizol, Dipyrone • Ibuprofen, Diclofenac Carbamazepine Gabapentin Amitriptylin Dexamethasone Lactulose Macrogol Haloperidol Metoclopramide

41. Pearls of wisdom • Sufficient pain reduction can normally be obtained using the principles of the WHO Pain Relief Ladder • Prefer administration of analgesics using the oral route • Change type and dosage of the drugs as necessary • Be aware of psychosocial elements influencing cancer pain • Don‘t be afraid of opioid related respiratory depression • Treat opioid induced side effects  

42. Reference list • Core Curriculum for Professional Education in PainJ. Edmond Charlton • Guide to Pain Management in Low-Resource-Settings IASP • The Pain Management Core Curriculum for European Medical Schools, Version October 2009 DGSS, EFIC • Medikamentöse Schmerztherapie bei Tumorpatienten, ein Leitfaden,10. überarbeitete Auflage E. Klaschnik

43. This talk was originally prepared by: Barbara Kleinmann, MD Freiburg, Germany

44. International Pain School Talks in the International Pain School include the following:

45. International Pain School The project is supported by these organizations: