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Pharmacologic Treatments of Pain

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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

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 Mr. Pain’s 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 1st chemotherapy (etoposide & cisplatin) with c/o abdominal pain. Chemotherapy is for palliative intent.

4 Mechanistic Approach to Pain
Somatic Superficial NOCICEPTIVE PAIN Deep Visceral MIXED Central Peripheral Nociceptive Pain Somatic: superficial somatic - skin invasion or ulceration deep somatic – bone, - muscle, soft tissue Visceral: organs NEUROPATHIC PAIN Others Ashby MA et al :

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 Caused by direct stimulation of peripheral nociceptors

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 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) Feldt Tool – used to assess pain in non-verbal patients Reference Feldt, K.S. (2000). Checklist of nonverbal pain indicators. Pain Management Nursing, 1(1), Current medication – dosage/frequency, effects, side effects. A list of prescribed and over the counter medications is valuable to determine what is working, what didn’t work, etc. Ask about any alternative or complementary medications that the patient may have taken or may be taking. BPI – Brief Pain Inventory; LANSS- ESAS - Edmonton Symptom Assessment System

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 What pharmacologic approach would you use?

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

11 Pharmacological: Opioids
*Codeine *Hydrocodone **Tramadol Morphine Hydromorphone Oxycodone Methadone Fentanyl Sufentanyl Levorphanol Meperidine Naloxone/Pentazocine Meperidine (demerol) Short duration Low analgesic potency p.o. High incidence of toxicity > 600mgs./24 hrs. Naloxone/Pentazocine (talwin) Limited oral bioavailability Psychomimetic s.e. high Never use with agonists Weak Opioids Opioids that can relieve mild to moderate pain, pain with a 4-6 score Usually mixed with other medicines such as acetaminophen or aspirin. Include hydrocodone, codeine, & tramadol. Eg. of weak opioids mixed with acetaminophyen or aspirin include Tylenol® with codeine, Fiorinal® with codeine, & Phenaphen® with codeine. Strong Opioids Opioids that can relieve severe pain, pain with a score of greater than 7 Other examples include fentanyl, methadone, levorphanol, hydromorphone, & oxycodone. Codeine combination products (>7 million prescriptions/yr) Oxycodone combination products (>1 million prescriptions/yr)

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

13 So, Where’s the roadmap?

14 The Analgesic Stepped Approach
Increasing Pain Severe Pain Moderate Pain Fentanyl Hydromorphone Methadone Morphine Oxycodone (+/- nonopioid) (+/- adjuvants) Mild Pain Codeine Oxycodone Tramadol (+/- nonopioid) (+/- adjuvants) The WHO Analgesic Ladder (Available at: recommends escalation from the use of non-opioid therapies, to opioids selective for moderate pain, and when pain persists, opioids for severe pain. Adjuvants are recommended as required. This three-step approach to the management of pain aims to provide “the right drug in the right dose at the right time”. Surgical intervention may also be necessary to provide further pain relief. Acetaminophen ASA NSAIDs/COXIBs (+/- adjuvants) World Health Organization. Cancer Pain Relief, with a Guide to Opioid Availability. Geneva, Switzerland: WHO, 1996. Leppert W, Luczak J. The role of tramadol in cancer pain management – a review. Support Care Cancer 2005;13:5-17.

15 Mr. Pain’s Story GP started him on hydromorphone contin ↓ in pain
developed hives, urticaria & constipation

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 Factors that we need to consider when initiating opioid therapy Patient exposure and experience-”I puked my guts out after they gave me morphine in the hospital after my surgery” Administration/Absorption-g-tubes,short gut syndrome Metabolism and Clearance-Renal dysfunction Opioid Profile-Special properties. Methadone as Agonist and NMDA receptor antagonist Fine PG. Journal of Pain, Aug. 2001

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 Available in oral liquid, IR tablets (2, 4, 8mg), CR capsules (3, 6, 12, 18, 24, & 30 mg), IR suppository, & injectable (1, 2, 4, 8mg/ml). Dilaudid (Hydromorphone) (Hydromorph Contin®) Sustained Release (Hydromorphone Injectable) Available 1, 2, 4, 8mg Given Q4H Available in 3mg suppository Available 3, 6, 12, 24, 30mg Given BID-TID Available 2, 10, 50mg vials PO SC butterfly Hydromorphone PO or Injectable dosage may also be doubled at HS to avoid waking patient through the night. CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Hydromorphone. Hydromorphorone is approximately 5-6 times more potent than Morphine. Sustained release opioids (Contin) should NOT be doubled at HS.

18 Pain & Substance Abuse Addiction Physical Dependence Tolerance
both physical & psychological components continuous craving & need for effects other than originally intended results in compulsive drug seeking behaviours the 4 C’s: impaired control over drug use, compulsive use, craving, continued use despite harm (consequences) 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 JCAHO pain standards at 1999 withdrawal: restlessness, tremors, rhinorrhea No predictable pattern of occurrence. In many ways, poorly understood. Risk of addiction is < 1% (Porter & Jick, 1980). Physical dependence results from continuous binding of exogenous opioids to opioid receptors. “a state of adaptation that often includes tolerance & is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, &/or administration of an antagonist. It is not the same thing as addiction. The symptoms of withdrawal include hypertension, nausea, vomiting, fever, shivering, diarrhea, and muscle aches. These symptoms can be minimized by slowly decreasing the dose of opioids. Weaning should be planned for any patient who has been taking opioids for more than one week.” (Taken from Accreditation Pain Standard: Making it Happen! Produced by The Canadian Pain Society) Addiction “is a primary, chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development & manifestations. Characterized by the 4 C’s.” Pseudoaddiction “is a term which has been used to describe patient behaviours that may occur when pain is undertreated. Patients with unrelieved pain may become focused on obtaining medications, may “clock watch”, and may otherwise seem inappropriately “drug seeking.” Even such behaviours as illicit drug use and deception can occur in the patient’s efforts to obtain relief. Psuedoaddiction can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated.” (Victoria House, 1998; Wickham, 2001)

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

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 These 3 methods are your preferred methods for chronic pain patients If they add on an Oxy 10mg q12h = 1 Percocet q6h – which all MD’s prescribing percocet would do So, why not start on a lower dose with the option of increasing the CR med?? May need to titrate more rapidly in cancer patient.

22 IR vs. CR Oral Opioids IR ORAL OPIOIDS CR ORAL OPIOIDS Onset of action
30 to 45 minutes ~ 2 hours Oxycodone has 45 minute onset Peak effect 60 minutes - - - Serum half-life 2 to 3 hours Duration of action 4 hours 12 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 IR vs. CR Oral Opioids IR Oral Opioids CR 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 Mr. Pain’s 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 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 Opioid Equianalgesic Doses
Oral Parenteral morphine 30 mg q3-4h around the clock OR 60mg q3-4h single or prn dosing 10 mg q3-4h codeine 130 mg q3-4h 75 mg q3-4 h hydromorphone 7.5 mg q3-4h 1.5 mg q3-4h meperidine 300mg q 2-3h 100 mg q3h oxycodone 30mg q 3-4h N/A in Canada Caution to docs switching from T3 to fentanyl to expect side effects such as sedation, in particular with patients that are opioid naïve Note that 7-10% of patients may not metabolize codeine and thus would then be considered opioid naïve There are many equianalgesic table…..they are guidelines MEDICATION P.O. DOSE Morphine 20 mg Codeine mg Oxycodone mg Hydromorphone 3-4 mg 60-134mg oral morphine /day = 25 ug/hr td fentanyl1 Jovey R. et al. Managing Pain. p. 109 1 Health Cnada, 2009

27 Choose another opioid Calculate the total dose of the analgesic over the past 24 hrs. If different routes have been used calculate separate totals. Calculate equivalent dose of new opioid Adjust starting dose of new opioid - consider ↓ initial dose by 25-50% if pain controlled by old opioid (no reduction if pain not controlled by old opioid) – accounts for incomplete cross-tolerance ÷ the dose by the # of administration x/day to obtain the interval dose Calculate BTP pain medication dose.

28 Morphine “Natural” drug derived from opium poppy.
It’s 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) Injectable Available 10, 20, 30, 40mg scored tabs, Given Q1H PRN, BTP (breakthrough pain), Suppository available in 10 & 20mg strengths Available in 15, 30, 60, 100, 200mg tabs Given BID/TID Suppository available in 30, 60, 100, 200mg strengths Ampules 10, 15, 50mg vials Given Q4H, PO/elixir, PO/PR/gel caps SC butterfly Morphine dosage may be doubled at HS (up to an equivalency of 40 mg PO Morphine Q4H) in order to avoid waking patient at 0200. CADD (Computerized Ambulatory Drug Delivery System) or Syringe Driver may be used to deliver a continuous dose of injectable Morphine. IV Route of Administration is NOT recommended due to its short lived effect, and greater potential for toxicity. Epimorphine is calculated and administered by anesthestist via pump for intractable pain in lower part of body (especially bilateral or midline pain). Kadian (Sustained Release) Available 20, 50, 100mg capsules. Given q24h. The patient’s pain should be stabilized on immediate release Morphine first. The dose should be equivalent to the patient’s total 24hr Morphine dose. Administer the initial dose of Kadian along with the last dose of immediate release Morphine. Capsules may be opened and sprinkled on soft food~~not chewed or crushed. Cannot be given rectally.

29 What next?

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 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 Sample titration schedule: 10, 20, 30, 40, 50, 60, 80, 100 mg q12h; can be titrated q24 hrs. μ& κ-opioidreceptor agonist Oxycodone Side Effects shallow breathing, slow heartbeat seizure (convulsions) cold, clammy skin confusion severe weakness or dizziness feeling light-headed, fainting nausea, vomiting, constipation, loss of appetite dizziness, headache, tired feeling dry mouth, sweating, itching IR: 5, 10, 15mg tablets CR: 10, 20, 40, 80mg Jovey, R. et al Managing Pain , Pg 96

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 Methadone, a synthetic opioid has some unique properties. It is the only truly long-acting opioid available (others depend on a controlled release mechanism). Methadone can be dosed once daily to prevent opioid withdrawal in opioid addicted people but is usually dosed q6-8h for pain. Extra caution is required when switching from another opioid to methadone due to a variable equianalgesic ratio. Naïve patients should be started on a small 5mg test dose before titrating. Use the “rules of 3” for safe titration: Never repeat a dose within 3 hours of a previous one, and never titrate the dose sooner than every 3 days. May cause ventricular arrhythmias (Torsades) in patients on higher doses who also have low Mg, K or Ca. It is metabolized by CYP450 3A4 enzyme. Many commonly prescribed drugs (Macrolides, Fluoroquinolones) may interfere with methadone metabolism and cause toxicity. See slide #83 for web site of drug interactions

33 Cytochrome P450 Drug Interaction Table
University of Indiana Department of Medicine This is an excellent website, updated regularly, which lists all of the major Cytochrome P450 drug interactions. Most opioids are metabolized by 2D6. Fentanyl and methadone are metabolized by 3A4.

34 Fentanyl Use if difficulty with oral meds; compliance issue; intractable side-effects 25ug. of Fentanyl range is mg oral morphine equivalents1 60mg of morphine or equivalent before switching to the 25ug. patch; 45mg if 12.5ug. patch. When applying 1st patch continue with other pain medication x 24 hrs. Rate of absorption can be affected by: fever, soap, oils, alcohol, shaving skin Duragesic/Fentanyl Patch Available in 25,50,75,100 µg/hr Applied q3days Topically on dry non hairy area back, chest upper arms When applying the initial patch the patient will require additional pain medication during the first 24 hours, as it is a slow released product. To be used in combination with short acting narcotics, such asMorphine for breakthrough painShould not be used in conjunction with sustained released opioidsRate of absorption may be affected by: ·Fever ·Soap ·Oils ·Lotions ·Alcohol ·Shaving skin If patch must be applied to a hairy area, clip hair with scissors do not shave. Apply patch and hold in place for 30 sec If patch falls off and is not damaged may reapply firmly by applying micropore tape OR a new patch may be applied Store at room temperature When removing, fold sticky sides together and flush down toilet Rotate patch sites Duragesic patch: 12.5, 25, 50, 75, 100 ug. 1Health Canada, January 2009

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. Possible side effects: respiratory changes, heart rhythm irregularity, peripheral vasodilation (blood pressure changes), inhibition of intestinal peristalsis (constipation), sphincter of Oddi spasm, & nausea/vomiting

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 Tylenol # 3 also contains caffeine.

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 There is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke. The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004) Zimmerman & Maddry, 1995 Seeff et al., 1986 Swarm et al., 2001 Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis2003;7:351-67 Latta, 2000 Garcia Rodriguez, Arthritis Res 2001; Curhan 2002 Watkins et al., 2006. Latta, 2000

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 Tramadol Side Effects seizure (convulsions) a red, blistering, peeling skin rash shallow breathing, weak pulse dizziness, drowsiness, weakness nausea, vomiting, constipation, loss of appetite blurred vision flushing (redness, warmth, or tingly feeling) sleep problems (insomnia)

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 XL1, 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 What is the appropriate intervention for Pain’s opioid therapy?
Discontinue morphine and initiate tramadol. Switch from MS Contin to OxyContin Administer MS Contin once a day, rather than every 12 hours Change dose of morphine and add a co-analgesic. Answer: Switch from MS Contin to oxycontin Tramadol Immediate release (IR) Start at 25mg./day, titrate slowly up to mg q4-6 hrs (max. 400mg/day) Rapid analgesic onset: start at mg q4-6 hrs (max. 400mg/day) Extended release If not on IR tramadol start at 100mg/day; titrate up to max. 300mg/day If on IR tramadol calculate 24 hr. dose & initiate total daily dose rounded down to nearest 100 mg, titrate up to max. of 300mg/day

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

42 Breakthrough Pain Always have BTP ordered: ensure it is adjusted if regular dose is adjusted. 30-50% 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 Based on Mr. Pain’s description of his pain, would you consider a co-analgesic?

44 What co-analgesic would you add to Mr. Pain’s pain management plan?
Baclofen Neurontin Zoledronic acid Nortiptyline

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

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 References: Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280: Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:

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 What Other Co-analgesics are there?

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 Reason for analgesic efficacy unclear Reduce membrane excitability Suppress abnormal discharges in pathologically-altered neurons Affects sodium channels Indications: acute and chronic neuropathic pain from peripheral nerve syndromes Trigeminal neuralgia Diabetic neuropathy Postherpetic neuralgia Efficacy with both lancinating and burning pain References: Simpson DM, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003;60: Eisenberg E, et al. Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001;57:

51 Pregablin (Lyrica) Indicated for the management of: Side Effects:
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) References: Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of pain neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280: Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA 1998;280:

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 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 Avoid cyclic antidepressants if QTc > 440 msec or if AV block

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 Acetaminophen is thought to act on the recently discovered COX-3 enzyme. It has been used over the counter for decades for the treatment of mild to moderate nociceptive pain. There is evidence for effectiveness in post operative pain. The maximum recommended daily dosage of acetaminophen is 4000 mg. Dosages in excess of 4000 mg per day risk hepatotoxicity by exceeding the ability of the liver to glucuronidate toxic metabolites. It is recommended that the daily dosage of acetaminophen be reduced to less than 3000 mg per day in patients with hepatic diseases such as hepatitis and cirrhosis. There is no actual published evidence for the commonly recommended dose ceiling of 4 gm / day of acetaminophen. Ken Latta, an academic pharmacist from Duke University has been collecting the literature on acetaminophen toxicity and has developed the above guidelines for the teaching hospitals affiliated with Duke. The risk of hepatotoxicity increases with 3 or more drinks of alcohol per day. (U.S. FDA Jan, 2004) -Evidence in postop pain: A single dose of 1000 mg had an NNT of 3.8 ( ) for at least 50% pain relief over 4-6 hours in patients with moderate or severe pain (a single dose of mg had an NNT of 4.6) Case, 2003; Zimmerman, 1995, 2000; Bromer, 2003; Perneger, 1994; Garcia Rodriguez, 2001; FDA Sept. 2002; Health Canada Feb. 2003; Curhan

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 Monotherapy for mild-moderate pain Co-analgesic for severe pain Effective in inflammatory arthritis Little long-term evidence in osteoarthritis Functions of prostaglandins: Protect gastric mucosa Support renal and platelet function Inflammation & pain response Pros and Cons of NSAIDs Optimal analgesia may require COX I and COX II1 Increased risk of CV events with COXIBs2, 3,4 COXIBs block prostacyclen but not thromboxane5 COXIBs have no antiplatelet activity and do not substitute for ASA Delayed healing of fractures in animals6 1. McCormack, 2002; 2. Mukheriee D. Jama 2001; 3. Howard PA, Jam Coll Cardiol, 2004; 4. Topol E, NEJM Marcus A.J. NEJM 2002; 6. Simon AM. JBMR 2002 Action: Both traditional COX-1 & -2 & selective COX-2 inhibit prostaglandin synthesis at peripheral sites of inflammation; central effect poorly understood Ibuprofen 400mg NNT of 2.4 ( ) ASA 650 mg: NNT pf 4.4 ( ) Diclofenac 50mg: NNT of 2.3 ( ) Naproxen 550mg: NNT of 2.6( ) NNT of at least 50% pain relief over 4-6hrs following single dose. Non-steroidal anti-inflammatory drugs can be very effective in the management of nociceptive pain association with tissue damage (including surgical pain) as well as inflammation. Reference for Ibuprofen: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose ibuprofen for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002. Reference for ASA: Edwards JE, Oldman A, Smith L, Collins SL, Carroll D, Wiffen P, McQuay HJ, Moore RA. Single dose Aspirin in acute pain. The Cochrane Library, Update Software, Oxford, 2000 (updated with no additional results 2002). Reference for diclofenac: Barden J, Edwards JE, Collins SL, McQuay HJ, Moore RA. Single dose diclofenac for postoperative pain. The Cochrane Library, Update Software, Oxford, 2002. Reference for naproxen: Mason L, Edwards, JE, Moore RA, McQuay HJ. Single dose naproxen for acute postoperative pain: a quantitative systematic review. BMC Anesthesiology 2003;3:4 A systematic review found that in most cases, the oral route of administration provides equivalent analgesia with fewer adverse effects compared to rectal and parenteral routes. Reference: Tramer M, Williams J, Carroll D, Wiffen PH, McQuay HJ, and Moore RA. Comparing analgesic efficacy of non-steroidal anti-inflammatory drugs given by different routes for acute and chronic pain. Acta Anaestheiologica Scandinavica 1998;42:71-79.

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

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 The problem with ASA must be underscored. In both the CLASS and VIGOR trials, concomitant use of ASA (as much as 325 mg per day) negates the GI protective effects of COXIBs. Given the widespread use of low-dose ASA, one has to wonder just how much safety benefit patients who use COXIBs actually obtain. For a good discussion on the subject, see: *McQuay HJ, Moore RA. Side effects of COX-2 inhibitors and other NSAIDs. In Proceedings of the 10th World Congress on Pain, Jonathon O. Dostrovsky, Daniel B. Carr, Martin Koltzenburg Eds. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle. **Chan FKL, Hung LCT, Suen BY, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347: Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ 2000;321: COXIBs = NSAIDs 10-17% of patients have increased BP1 Acute and chronic renal toxicity2 Double the risk of hospitalization for CHF3 Delayed gestation Increased miscarriage risk4 No evidence in neuropathic pain 1. Cheng HF. Hypertension, 2004; 2. DeMaria AN. JPSM 2003; 3. Garcia-Rodriguez LA. Epidemiology 2003; 4. Li DK. BMJ 2003 *McQuay HJ, Moore RA.. In Proceedings of the 10th World Congress on Pain. Jonathon O. et al. Progress in Pain Research and Management Volume 24, pp , IASP Press, Seattle. **Chan FKL, et al. N Engl J Med 2002;347: *Taking ASA nullifies the GI protective effect of COXIBs

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 Cytoprotective Agents
Sucralfate (1gm Qid) misoprostol (200ug Qid) * not best choice H2 receptor antagonists eg. Cimetidine, ranitidine Omperazole 20-40mg/day

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 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 Van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the cochrane collaboration. Spine Sep 1;28(17): Mao J, Chen LL. Systemic lidocaine for neuropathic pain relief. Pain Jul;87(1):7-17. Kalso E, Tramer MR, McQuay HJ, Moore RA. Systemic local-anaesthetic-type drugs in chronic pain: a systematic review. Eur J Pain Mar;2(1): Smith HS, Barton AE. Tizanidine in the management of spasticity and musculoskeletal complaints in the palliative care population. Am J Hosp Palliat Care Jan-Feb;17(1):50-8. Review. Lang A.M. Botulinum toxin type A therapy in chronic pain disorders. Arch Phys Med Rehabil Mar;84(3 Suppl 1):S69-73; quiz S74-5. Review.

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? Discuss the acute side effects with patients before prescribing. They are more likely to persist if they know that the acute side effects are temporary. Be proactive with side effects

64 Side Effects of Opioids
COMMON LESS COMMON RARE Side effect Nausea and vomiting Constipation Sedation and drowsiness Confusion Myoclonus Dry mouth Urinary retention Sweats GE reflux Pruritus Respiratory depression (very rare in properly titrated patients) Note: Long term side effects of chronic use covered in later section. Respiratory depression issue in opioid naïve patients given improper doses, i.e. medication errors. Case of girl at Sick Kids in Toronto receiving 10 mg IV instead of 1 mg IV precipitating respiratory arrest and death.

65 Treatment of Common Opioid Side Effects
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 Constipation-highlight differences in management between cancer and non-cancer population (ie more aggressive use of bowel stimulants in cancer patients) Lack evidence to support the use of docusate in relieving constipation See reference section for treatment of side effects document Discuss pros and cons of each antiemetic. Use drugs of choice from your practice

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 Mr. Pain’s Story Presented for his 2nd chemotherapy tx. with well controlled pain. Reported taking fewer BTP medication, once or twice q3-4 days. Oncologist decreased his pain medication. At this point you need to determine what is happening…..time to reassess, readdress Determine what is happening, treat the underlying disease. It is a common occurrence that patients spontaneously discontinue their own meds-sometimes up to 1/3 of them Decreasing Dose or Discontinuing Opioids Possible Indications Dramatic decrease in pain Increase in side effects despite stable dosage Resolution of underlying problem Active addiction If patient wants to discontinue

68 Opioid Dose Reduction Careful reduction to decrease opioid toxicity – monitor pain control Dose reduction may include the concurrent addition of adjuvant analgesics Tapering Schedule First 48 hours: decrease daily dose of opioid by 50% in Second 48 hours: *decrease daily dose by 25% (assuming no increase in pain) Third 48 hours: *decrease daily dose by 25% May prescribe IR opioids to minimize interdose pain or withdrawal symptoms Remember this is a non fatal withdrawal In tools section there is a two page document title “managing opioid withdrawal” that can be utilized…….this is an alternate and slower method than the one mentioned above. 10% reduction per day, per week, per month, etc. Slow dose reduction at the end of the wean. Use Clonidine for withdrawal symptoms. Use Clonazepam for withdrawal symptoms. Methadone withdrawal symptoms may persist after end of withdrawal.

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 Putting it Altogether A. 15 mg BID B. 30 mg BID C. 45 mg BID
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 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 If there is a question with regard to “no ceiling dose” how would you respond? no pharmacological ceiling dose Limitations may be based on side effects The key is to document well the need/outcome of a high dose consider dosing as dynamic not static ** If the MD has a “personal” dose ceiling that the patient has reached and the patient remains less than well controlled, this may be an indication for a consult**


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