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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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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

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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 2002 - 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.

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Mechanistic Approach to Pain

Somatic

MIXED

Ashby MA et al. 1992 51:153-161

NOCICEPTIVEPAIN

Visceral

Superficial

Deep

NEUROPATHIC PAIN

Peripheral

Others

Central

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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

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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

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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

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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.

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What pharmacologic approach would you use?

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Your Selection

Opioids

Non-Opioid Analgesics

Adjuvant Medications (Co-analgesics)

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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)

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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)

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So, Where’s the roadmap?

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CodeineOxycodoneTramadol(+/- nonopioid)(+/- adjuvants)

AcetaminophenASANSAIDs/COXIBs(+/- adjuvants)

The Analgesic Stepped Approach

World Health Organization. Cancer Pain Relief, with a Guide to OpioidAvailability. 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.

MildPain

ModeratePain

Severe Pain

Increasing Pain

FentanylHydromorphoneMethadoneMorphineOxycodone(+/- nonopioid)(+/- adjuvants)

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Mr. Pain’s Story

• GP started him on hydromorphone contin

• ↓ in pain

• developed hives, urticaria & constipation

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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

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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

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Pain & Substance AbusePhysical 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 C’s: impaired control over drug use, compulsive use, craving, continued use despite harm (consequences)

(Victoria House, 1998; Wickham, 2001)

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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

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

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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

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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

CommentsQ6h dosing causes

sub-therapeutic intervals

Monitor for end-of-dose failure

Note: These studies were conducted in healthy volunteers, or post-op

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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

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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.

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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”

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Opioid Equianalgesic Doses

Opioid Oral Parenteral

morphine30 mg q3-4h around the clock OR 60mg q3-4h

single or prn dosing10 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

60-134mg oral morphine /day = 25 ug/hr td fentanyl1

Jovey R. et al. Managing Pain. p. 109

1 Health Cnada, 2009

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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)

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What next?

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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 tabletsCR: 50, 100, 150, 200mg tablets

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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 tabletsCR: 10, 20, 40, 80mg

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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

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Cytochrome P450 Drug Interaction Table

University of Indiana

Department of Medicine

www.drug-interactions.com

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Fentanyl• Use if difficulty with oral meds; compliance issue;

intractable side-effects

• 25ug. of Fentanyl range is 60 - 134 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

1Health Canada, January 2009

Duragesic patch: 12.5, 25, 50, 75, 100 ug.

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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.

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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

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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 http://pain.mc.duke.edu/mild_pain.cfm

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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

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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

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What is the appropriate intervention for Pain’s 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.

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Drug Selected: Oxycodone

• Oxycontin 60mg (40mg & 20mg) BID

• Oxy-IR 10mg q1hr. prn for BTP

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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.

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Based on Mr. Pain’s description of his pain, would you consider a co-

analgesic?

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What co-analgesic would you add to Mr. Pain’s pain management

plan?

1. Baclofen

2. Neurontin

3. Zoledronic acid

4. Nortiptyline

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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

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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

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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

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Neurontin

• 100-300mg 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 1800-3600mg

• Supplied in 100mg, 300mg, 400mg, 600mg, 800mg capsules

• Dose reduction needed in renal compromise

• Morphine increases the neurontin concentration in the blood

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What Other Co-analgesics are there?

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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 100-200mg BID

• Valproate 250mg daily to TID

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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)

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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.

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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

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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.

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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

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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)

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NSAIDs

• Side effects

• Contraindications

• GI distress

• Bleeding 2° to platelet dysfunction

• Renal failure

• Bronchoconstriction

• ? Delay in bone healing

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Which one?• Ketoprofen (Orudis) – 150-200mg daily (RA & OA); 50mg TID-

QID (menstrual cramps & mild-to-moderate pain)

• Indomethacin (Indocid) – 25mg BID - TID

• Ibuprofen (Motrin) – 200-800mg TID

• Toradol (Ketorolac) – 10mg q4-6hr

• Naproxen (Naprosyn) – 250-500mg BID

• Diclofenac (Voltaren) – 25-50mg TID or 75mg SR daily (maximum dose 150mg)

• ASA – 325-650mg QID/q4hr

• Rofecoxib (Vioxx) - Sept. 2004 removed from market

• Celecoxib (Celebrex) – 100-200mgQD-BID

*Taking ASA nullifies the GI protective effect of COXIBs

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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.

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Cytoprotective Agents

• Sucralfate (1gm Qid)

• misoprostol (200ug Qid) * not best choice

• H2 receptor antagonists eg. Cimetidine, ranitidine

• Omperazole 20-40mg/day

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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

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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

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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?

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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)

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Treatment of Common Opioid Side Effects

TREATMENT

Nausea and vomiting

•Ondansetron 8mg q8hr prn

•Haloperidol 0.5-1.0 mg od-tid

•Phenothiazine 5-10 mg PO q4-6h prn•Dimenhydrinate often too sedating

• If motility is an issue

– Metoclopramide 10-20 mg qid

Constipation

• Use dietary measures first (bran, flax, prunes)

– Osmotics-MOM, lactulose

– Stool softeners - docusate

– Stimulants-senna, bisacodyl

– Suppositories-dulcolax

– Enemas

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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

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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.

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Opioid Dose Reduction

• Careful reduction to decrease opioid toxicity – monitor pain control

• Dose reduction may include the concurrent addition of adjuvant analgesics

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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

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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 BIDB. 30 mg BIDC. 45 mg BIDD. 60 mg BID

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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

• www.painCare.ca

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THANK YOU