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1 Pharmacologic Treatments of Pain PMRC Nursing Module Kim Chapman RN, MSc(N), CON(C) Clinical Nurse Specialist, Oncology October 2, 2009.

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Presentation on theme: "1 Pharmacologic Treatments of Pain PMRC Nursing Module Kim Chapman RN, MSc(N), CON(C) Clinical Nurse Specialist, Oncology October 2, 2009."— Presentation transcript:

1 1 Pharmacologic Treatments of Pain PMRC Nursing Module Kim Chapman RN, MSc(N), CON(C) Clinical Nurse Specialist, Oncology October 2, 2009

2 2 Learning Objectives Understand the spectrum of pain pharmacology Choose pharmacologic treatment options in chronic and cancer pain Identify the more common side effects and strategies to manage those side effects

3 3 Mr. Pains Story 57 yr. old male diagnosed with small cell lung cancer. Has a lg. mass in his LUL along with mediastinal & (lt.) hilar adenopathy, extensive liver mets. MI in takes ASA daily; peptic ulcer disease - takes losec daily Active until about 1 mos. ago. Lost ~10 lbs. in the last 2-3 mos. Poor nutritional intake. Constipated. ++ ascites. Enlarged liver. Jaundiced. Arrived for day 1 of his 1 st chemotherapy (etoposide & cisplatin) with c/o abdominal pain.

4 4 Mechanistic Approach to Pain Somatic MIXED Ashby MA et al : NOCICEPTIVE PAIN Visceral Superficial Deep NEUROPATHIC PAIN Peripheral Others Central

5 5 Nociceptive: Somatic pain skin, muscle, connective tissue or bone dull, sharp, aching, stabbing, throbbing, or pressure well-localized usually associated with tissue damage as well as inflammatory processes eg. bone mets., pressure ulcer, infiltrated IV, incision Nociceptive: Visceral pain organs or tissue gnawing, cramping, aching, sharp, colicky, dull, or sharp localized or referred eg. hepatomegaly, bladder spasms

6 6 Neuropathic pain nerve involvement centrally or peripherally may arise as a direct consequence of a lesion or disease affecting the somatosensory system (IASP 2007) sharp, tingling, burning, shooting, pins & needles, allodynia, burning, or lancinating

7 7 Pain Assessment Findings P – Provocation & Palliation – lying, hiccups; certain positioning, heat, medication, relief of hiccups, relief of anxiety, sleep (BPI) Q – Quality of Pain - Classic neuropathic pain both anterior thigh areas with the usual burning, stinging, & sharp pain along with allodynia - possibly due to femoral nerve obstruction or paraneoplastic syndrome. (LANSS). Dull, achy pain in abdominal area - nociceptive pain (BPI) R – Region & Radiation - Pain moves from place to place; always persistent (BPI) S – Severity (on a 0-10 scale) - Pain score of 8-9 at rest and 10 + with activity (ESAS & BPI) T – Timing – constant unless using pain medication; time of day does not appear to influence pain experience (BPI) BPI – Brief Pain Inventory; LANSS- ESAS - Edmonton Symptom Assessment System

8 8 Key Patient Outcomes Mr. Pain verbalizes that pain is reduced or relieved to his satisfaction. Mr. Pain uses pharmacologic and non- pharmacologic interventions. Mr. Pain participates in activities of daily living with appropriate medications.

9 9 What pharmacologic approach would you use?

10 10 Your Selection Opioids Non-Opioid Analgesics Adjuvant Medications (Co-analgesics)

11 11 Pharmacological: Opioids *Codeine *Hydrocodone **Tramadol Morphine Hydromorphone Oxycodone Methadone Fentanyl Sufentanyl Levorphanol Meperidine Naloxone/Pentazocine Codeine combination products (>7 million prescriptions/yr) Oxycodone combination products (>1 million prescriptions/yr)

12 12 Pharmacological: Non-Opioid Analgesics –Acetaminophen –NSAIDS (Anti- inflammatory medications) Adjuvant Medications (Co-analgesics) –Anticonvulsants (carbamazepine, phenytoin, gabapentin, pregabalin) –Antidepressants (amitriptyline, nortriptyline, desipramine) –NMDA blockers –Corticosteroids (dexamethasone) –Antispasmodic agents (baclofen) –Bisphosphonates (pamidronate, zoledronic acid)

13 13 So, Where s the roadmap?

14 14 Codeine Oxycodone Tramadol (+/- nonopioid) (+/- adjuvants) Acetaminophen ASA NSAIDs/COXIBs (+/- adjuvants) The Analgesic Stepped Approach World Health Organization. Cancer Pain Relief, with a Guide to Opioid Availability. Geneva, Switzerland: WHO, Leppert W, Luczak J. The role of tramadol in cancer pain management – a review. Support Care Cancer 2005;13:5-17. Mild Pain Moderate Pain Severe Pain Increasing Pain Fentanyl Hydromorphone Methadone Morphine Oxycodone (+/- nonopioid) (+/- adjuvants)

15 15 Mr. Pains Story GP started him on hydromorphone contin in pain developed hives, urticaria & constipation

16 16 Opioid Therapy: Getting Started Basic Considerations: Patient opioid exposure & experience Patient fears (stigma) Caregiver & physician attitudes, preferences & biases Compliance Convenience Cost Side effects Pharmaco-clinical Considerations: Patient sensitivities/allergies Administration & absorption limitations Metabolism & clearance Opioid profile Fine PG. Journal of Pain, Aug. 2001

17 17 Hydromorphone: Key Points ~ 5 x more potent than morphine Fewer drug interactions May be used cautiously in renal failure Very soluble - up to 300 mg/ml Available in oral liquid, IR tablets, CR capsules, IR suppositories, & injectable form. Less sedation, less pruritis, less constipation & vomiting than morphine

18 18 Pain & Substance Abuse Physical Dependence pts. are physically acclimatized to the presence of the drug occurs with long-term opioid use pts will experience withdrawal if drug is withheld if opiod withdrawn quickly then withdrawal Predictable Tolerance Given dose that relieved pain no longer produces the same degree and duration of relief Addiction both physical & psychological components continuous craving & need for effects other than originally intended results in compulsive drug seeking behaviours the 4 Cs: impaired control over drug use, compulsive use, craving, continued use despite harm (consequences) (Victoria House, 1998; Wickham, 2001)

19 19 Screening for Addiction/Misuse Risk Previous history of substance abuse/addiction Family history of drug abuse &/or addiction Previous chemical coping with life stresses Significant psychiatric history Previous high risk behaviours (esp. criminal activity) High risk home environment

20 20 Which opioid(s) would you use with Mr. Pain?

21 21 Opioid Therapy: Which Approach? Start with an IR opioid & titrate to effect When dose stable CR opioid –fastest method for pain relief Start with CR opioid & titrate dose q 1-3 days (or when side effects stable) –for stable, chronic pain Start with CR opioid baseline dose & use IR opioid to titrate –once weekly (may be as soon as q2-4 days in patients with cancer), add the total daily dose of IR to the CR dose and repeat weekly until dose stable

22 22 IR vs. CR Oral Opioids IR ORAL OPIOIDSCR ORAL OPIOIDS Onset of action30 to 45 minutes ~ 2 hours Oxycodone has 45 minute onset Peak effect60 minutes- - - Serum half-life 2 to 3 hours- - - Duration of action4 hours12 to 24 hours Comments Q6h dosing causes sub-therapeutic intervals Monitor for end-of-dose failure Note: These studies were conducted in healthy volunteers, or post-op

23 23 IR vs. CR Oral Opioids IR Oral OpioidsCR Oral Opioids Advantages Quick onset Allows for quick titration (as early as every 24 hours) Convenience and compliance Uninterrupted sleep Disadvantages Frequent dosing Interrupted sleep Slower titration (48 to 72 hours) Slower elimination in event of severe side effects

24 24 Mr. Pains Story GP switched to an equianalgesic dose of morphine i.e. 100mg BID. Uticaria disappeared. No change in hives or constipation. c/o mild, infrequent nausea. Started to become agitated & experienced hallucinations.

25 25 Opioid Rotation Changing one opioid to another When: if pain is or has been relieved with original opioid, but toxicity limits further dose titration Approximate dose ratio of two opioids required to produce a similar degree of analgesia –equianalgesic tables

26 26 Opioid Equianalgesic Doses OpioidOralParenteral morphine 30 mg q3-4h around the clock OR 60mg q3-4h single or prn dosing 10 mg q3-4h codeine 130 mg q3-4h75 mg q3-4 h hydromorphone 7.5 mg q3-4h1.5 mg q3-4h meperidine 300mg q 2-3h100 mg q3h oxycodone 30mg q 3-4hN/A in Canada mg oral morphine /day = 25 ug/hr td fentanyl 1 Jovey R. et al. Managing Pain. p Health Cnada, 2009

27 27

28 28 Morphine Natural drug derived from opium poppy. Its the old standard NOT the gold standard. Very effective orally (first pass through liver). Duration of action for oral IR is ~ 4 hrs. & parenteral is ~ 3-4 hrs. Active metabolites may accumulate in renal insufficiency leading to toxicity; not recommended in renal failure. Fluctuating plasma levels can lead to variable efficacy & side effects. In the elderly bioavailability can be as low as 30%. More sedating & GI s.e. than the semi-synthetic opioids. More CNS effects in elderly (sedation, confusion, hallucinations) Histamine release (pruritis)

29 29 What next?

30 30 Codeine 10% of the overall population lacks the enzyme (CYP450 2D6) required to metabolize codeine to active drug morphine 2-5% of the population have relatively high amounts of the converting enzyme Ceiling dose is 600 mg/day Most constipating of all opioids Some SSIs (Paxil, Prozac, Cymbalta) inhibit the conversion of codeine to morphine IR: 15mg, 30mg, 60mg tablets CR: 50, 100, 150, 200mg tablets

31 31 Oxycodone Hydrochloride Strong semisynthetic opioid; potency 2x > morphine Conversion to oxymorphone may be inhibited by drugs such as fluoxetine CR form is OxyContin ®. Dose initiation: 10mg q12h for opioid naïve No pharmacological dose ceiling for pure opioid agonists. Can be used with close monitoring in renal failure Jovey, R. et al Managing Pain 2008, Pg 96 IR: 5, 10, 15mg tablets CR: 10, 20, 40, 80mg

32 32 Methadone Powder, capsule, liquid, suppositories Long half-life (q8h). Half-life variable making it unpredictable with repeated doses sudden severe toxicity. Variable equianalgesic dose to other opioids Individual titration with close monitoring is extremely important Special authorization from Health Canada Many drug interactions with CYP450 3A4 Less constipating; does not cause metabolite accumulation; less expensive A good option in neuropathic pain

33 33 Cytochrome P450 Drug Interaction Table University of Indiana Department of Medicine

34 34 Fentanyl Use if difficulty with oral meds; compliance issue; intractable side-effects 25ug. of Fentanyl range is mg oral morphine equivalents 1 60mg of morphine or equivalent before switching to the 25ug. patch; 45mg if 12.5ug. patch. When applying 1 st patch continue with other pain medication x 24 hrs. Rate of absorption can be affected by: fever, soap, oils, alcohol, shaving skin 1 Health Canada, January 2009 Duragesic patch: 12.5, 25, 50, 75, 100 ug.

35 35 Sufentanil (sufenta) Approximately 5 to 10 times more potent than fentanyl Relieves pain by stimulating opiate receptors in CNS25-50 mcg SL/buccal. Good choice for use just before activity. Pt. teaching re: taking it.

36 36 Tylenol # 3 300mg acetaminophen + 30mg of codeine in each tablet 12 x Tylenol #3 (usual daily dose) = 3.6g total daily dose of acetaminophen & 360mg of codeine – this exceeds what is safely recommended for chronic use in healthy patients

37 37 Acetaminophen*- Suggested Dose Ceilings 4 gm/day > 10 days in healthy, well-nourished patients – short-term use in healthy patients 3.2 gm / day for chronic use in healthy patients 2.6 gm / day chronically in at risk patients *Daily alcohol consumption, warfarin, fasting, a low protein diet, cardiac or renal disease increase the risk of hepatotoxicity Latta, 2000

38 38 Tramadol An opioid analgesic with a dual mechanism of action (weak affinity to the Mu receptor + inhibits the reuptake of serotonin & norepinephrine) Recommended for the tx. of moderate - moderately severe pain. CR tramadol can be initiated in opioid naïve at lowest dose Less constipating then codeine Maximum 400mg/day

39 39 Tramadol Dosing Immediate release (Tramacet) –One tablet is 37.5mg Tramadol HCL/ 325mg of acetaminophen –Maximum dose is 8 tablets per 24hours –Beneficial for acute pain Extended release (Zytram XL 1, Ralivia, Tridural) –Doses 100mg, 150mg, 200mg, 300mg, and 400mg –If on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 400mg/day

40 40 What is the appropriate intervention for Pains opioid therapy? 1.Discontinue morphine and initiate tramadol. 2.Switch from MS Contin to OxyContin 3.Administer MS Contin once a day, rather than every 12 hours 4.Change dose of morphine and add a co- analgesic.

41 41 Drug Selected: Oxycodone Oxycontin 60mg (40mg & 20mg) BID Oxy-IR 10mg q1hr. prn for BTP

42 42 Breakthrough Pain Always have BTP ordered: ensure it is adjusted if regular dose is adjusted % of regular dose q4hrs. (you may want to use 1/10 to 1/6 of the total daily dose usually q1hr.) Same drug is usually used; may use other drugs. >/= 3 doses BTP/24 hours add to regular dose If pain is not improved after 1-2 BTP increments re-evaluate cause of pain.

43 43 Based on Mr. Pains description of his pain, would you consider a co- analgesic?

44 44 What co-analgesic would you add to Mr. Pains pain management plan? 1.Baclofen 2.Neurontin 3.Zoledronic acid 4.Nortiptyline

45 45 What was Prescribed? Neurontin (gabapentin) –100mg BID x 2 days –100mg TID x 2 days –200mg TID daily Baclofen 5mg q8hr Senokot-S 2 tabs. at hs

46 46 Which of the following side effects will you need to monitor when neurontin is initiated? 1.Constipation, nausea, itching, tremors, and hallucinations 2.Sedation, dizziness, nausea, confusion, and lower extremity edema 3.Ataxia, nausea, alterations in liver enzymes, and weight gain 4.Ataxia, nausea, vomiting, and diarrhea

47 47 Neurontin Proven indications: postherpetic neuralgia (PHN) & diabetic neuropathy Widely considered to be first-line (co-analgesic) agent for neuropathic pain despite off label status Fewest drug interactions of all AEDs Common adverse effects: somnolence, dizziness, fatigue, ataxia, S & S of CNS depression

48 48 Neurontin mg mg qhs; PHN initiate at 300mg day 1, 600mg day 2 in divided dose, 900mg day 3 in divided dose, & titrated further as needed up to mg Supplied in 100mg, 300mg, 400mg, 600mg, 800mg capsules Dose reduction needed in renal compromise Morphine increases the neurontin concentration in the blood

49 49 What Other Co- analgesics are there?

50 50 Antiepileptic Drugs Neurontin Pregablin (lyrica) Lamotrigine –Well-tolerated with proven efficacy in neuropathic pain caused by neurotoxic anti-retroviral therapy in HIV-positive patients Carbamazepine mg BID Valproate 250mg daily to TID

51 51 Pregablin (Lyrica) –Indicated for the management of: Neuropathic pain associated with diabetic peripheral neuropathy Postherpetic neuralgia PHN) –Side Effects: dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention)

52 52 Pregablin (Lyrica) –Available: 25mg, 50mg, 75mg,150mg, 300mg –Recommended dose/day: 150mg, 300mg, 600mg PHN patients who tolerate LYRICA may benefit from up to 600 mg/day after 2 to 4 weeks of treatment with 300 mg/day –May take up to a week to receive benefit. –May exacerbate the effects of oxycodone, lorazepam, or ethanol on cognitive & gross motor functioning. –Discontinue gradually over a minimum of 1 week.

53 53 Cyclic Antidepressants Amitriptyline –Best-established efficacy; most widely used for pain –Highest anticholinergic s.e. profile of all cyclic antidepressants –Common s.e.: sedation, constipation, dry mouth, blurred vision, urinary retention –10-25mg mg qhs Nortriptyline –Less sedation & anticholinergic side effects than amitriptyline –Common adverse effects include sedation, dry mouth, constipation –10-25mg qhs Desipramine –Tolerability & efficacy similar to that of nortriptyline –Less anticholinergic side effects than amitriptyline 25mg qhs

54 54 Non-Opioid Analgesics: Acetaminophen Used for mild-moderate nociceptive pain Dose ceiling 2 key side effects: renal toxicity & risk for hepatotoxicity Usual dose: 325mg 1-2 tabs q4-6h Case, 2003; Zimmerman, 1995, 2000; Bromer, 2003; Perneger, 1994; Garcia Rodriguez, 2001; FDA Sept. 2002; Health Canada Feb. 2003; Curhan 2002.

55 55 NSAIDS # & diversity have increased over the past 20 yrs. Evidence detailing effectiveness is contradictory – COX I & COX II Analgesic & anti-inflammatory effects Routes: Oral preferred, IV faster onset Ceiling Dose

56 56 NSAIDs/COXIBs Increase risk of exacerbation of underlying renal insufficiency Increase risk of fluid retention Increase risk of cardiovascular complications Increase risk of GI bleeds (especially NSAIDs in patients requiring concomitant ASA for cardiovascular prophylaxis)

57 57 NSAIDs Side effects Contraindications GI distress Bleeding 2° to platelet dysfunction Renal failure Bronchoconstriction ? Delay in bone healing

58 58 Which one? Ketoprofen (Orudis) – mg daily (RA & OA); 50mg TID- QID (menstrual cramps & mild-to-moderate pain) Indomethacin (Indocid) – 25mg BID - TID Ibuprofen (Motrin) – mg TID Toradol (Ketorolac) – 10mg q4-6hr Naproxen (Naprosyn) – mg BID Diclofenac (Voltaren) – 25-50mg TID or 75mg SR daily (maximum dose 150mg) ASA – mg QID/q4hr Rofecoxib (Vioxx) - Sept removed from market Celecoxib (Celebrex) – mgQD-BID *Taking ASA nullifies the GI protective effect of COXIBs

59 59 Toradol Suggested for moderate pain. Recommended as an alternative to low- dose opioids. Suggested to limit oral use x 7 days or parenteral to 2 days. Major s.e. are GI; need something for GI side-effect prevention.

60 60 Cytoprotective Agents Sucralfate (1gm Qid) misoprostol (200ug Qid) * not best choice H 2 receptor antagonists eg. Cimetidine, ranitidine Omperazole 20-40mg/day

61 61 Is an NSAID a good choice for Mr. Pain? History of ulcer complications Multiple NSAIDS High-dose NSAIDS Concomitant anticoagulant use Age >/= 60yrs. Concomitant corticosteroid use History of cardiovascular disease

62 62 Other Medications for Pain Muscle relaxants –Cyclobenzaprine, Baclofen Local anesthetic congeners –IV Lidocaine, oral Mexiletine NMDA (N-methyl D-aspartate) blockers –Dextromethorphine, ketamine Alpha-2 agonists –Clonidine, Tizanidine Botulinum Toxin

63 63 Mr. Pain has already experienced uticaria, rash, constipation, agitation, & hallucinations from his opioid therapy. What other side effects might you anticipate with ongoing opioid therapy?

64 64 Side Effects of Opioids COMMONLESS COMMONRARE Side effectNausea and vomiting Constipation Sedation and drowsiness Confusion Myoclonus Dry mouth Urinary retention Sweats GE reflux Pruritus Respiratory depression (very rare in properly titrated patients)

65 65 Treatment of Common Opioid Side Effects TREATMENT Nausea and vomiting Ondansetron 8mg q8hr prn Haloperidol mg od-tid Phenothiazine 5-10 mg PO q4-6h prn Dimenhydrinate often too sedating If motility is an issue –Metoclopramide mg qid Constipation Use dietary measures first (bran, flax, prunes) –Osmotics-MOM, lactulose –Stool softeners - docusate –Stimulants-senna, bisacodyl –Suppositories-dulcolax –Enemas

66 66 Opioid Neurotoxicity Presents as agitation, confusion, myoclonus, hallucinations & rarely seizures Possible precipitants –Infection/Sepsis –Dehydration –Decreased renal clearance –Rapid dose escalation Management: dose or hold medication until sensorium clears, Opioid rotation, Consider hydration with both options

67 67 Mr. Pains Story Presented for his 2 nd chemotherapy tx. with well controlled pain. Reported taking fewer BTP medication, once or twice q3-4 days. Oncologist decreased his pain medication.

68 68 Opioid Dose Reduction Careful reduction to decrease opioid toxicity – monitor pain control Dose reduction may include the concurrent addition of adjuvant analgesics

69 69 Putting it Altogether Susan has been receiving hydromorphone 2 mg s/c. She is now able to tolerate oral medication. The best option for the oral dose would be: A. 1 mg B. 2 mg C. 4 mg D. 8 mg

70 70 Putting it Altogether Jane has been taking 10 mg. of morphine by mouth q4hr with good relief. A decision has been made to switch her to a sustained release morphine. The starting dose should be: A. 15 mg BID B. 30 mg BID C. 45 mg BID D. 60 mg BID

71 71 Take Home Pearls Assessment is key. Goal is to reduce pain to an acceptable level. Involve the patient in goal setting & negotiating analgesic strategies. Do not delay treating pain – avoid chronic pain. A multi-modal approach is recommended (pharm & non-pharm). Prevention is better than treatment – give meds regularly. Use least invasive route possible & avoid IM injections. Anticipate & manage side effects


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