Adjuvant Analgesics In

Palliative And End-Of-Life

CareMike Harlos MD, CCFP, FCFPProfessor and Section Head, Palliative Medicine, University of ManitobaMedical Director, WRHA Palliative CareMedical Director, Pediatric Symptom Management Service

Case Presentation

55 yo man Metastatic CA lung, large L apical tumour Chemotherapy completed, no response Metastatic disease to bone, liver Presents with worsening L arm pain and

numbness, allodynia, tingling and burning Motor exam normal

Case PresentationCurrent Medications

Morphine 100 mg po q4h

Ibuprofen over the counter

Sennosides, docusate

Adjuvant Analgesics

first developed for non-analgesic indications

subsequently found to have analgesic activity in specific pain scenarios

Common uses: pain poorly-responsive to opioids (eg.

neuropathic pain), or with intentions of lowering the total

opioid dose and thereby mitigate opioid side effects.

Adjuvants Used In Palliative Care

General / Not specific corticosteroids cannabinoids (very uncommonly used)

Neuropathic Pain gabapentin antidepressants topiramate ketamine clonidine

Bone Pain bisphosphonates (calcitonin)

inflammationedema

spontaneous nerve depolarization

tumor mass effects

CORTICOSTEROIDS AS ADJUVANTS

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IMMEDIATE LONG-TERM Psychiatric Hyperglycemia risk of GI bleed

gastritis aggravation of

existing lesion (ulcer, tumor)

Immunosuppression

Proximal myopathy often < 15 days

Cushing’s syndrome

Osteoporosis Aseptic /

avascular necrosis of bone

CORTICOSTEROIDS: ADVERSE EFFECTS

DEXAMETHASONE

• minimal mineralcorticoid effects

• po/iv/sq/?sublingual routes

• perhaps can be given once/day; often given more frequently

• If an acute course is discontinued within 2 wks, adrenal suppression not likely

Cannabinoids

As

Adjuvants

Cannabis sativa

Marijuanadried leaves, flowers

Hashishresin from leaves, buds

Isolated pure compounds (>400)

Noncannabinoids Cannabinoids

Psychoactive• 8-THC• 9-THC• cannabinol

Active, not psychoactive• cannabidiol

Inactive• > 60

Kalant, Pain Res Manage 2001

THC contentapprox. 5%

THC content10 – 20%

Cannabinoid ReceptorsCB1 And CB2

CB1 Central and peripheral nervous system Highest density in globus pallidus, basal

ganglia, substantia nigra, cerebellum, hippocampus, afferent spinal cord pathways

Main effect is neurotransmitter release –dopamine, NE, serotonin

Low levels in cardiorespiratory centres high therapeutic index

CB2 – certain nonneural tissues, eg. immune cells Cannabinoids also bind to NMDA receptors –

possible role in neuropathic pain

Kumar et al, Anaesthesia 2001; 56

The only clinical indication is in chemotherapy-induced nausea

Mixed results in human studies for pain control; animal studies suggest possible role for neuropathic pain

Double-blind, placebo-controlled trials indicate a similar analgesic potency to codeine, however high adverse effects

Cannabinoids

Marijuana Use in Pain

Five RCTs on cancer pain Tetrahydrocannabinol (THC) or nabilone

vs placebo or opioids High rate of side effects 128 pts total, single dose x-over design THC = codeine (60, 120 mg) > placebo Nabilone > placebo Higher doses had unacceptable S/E Poor evidence for pain control

Campbell et al, BMJ 323:13-16, 2001

Marijuana - Acute Effects

Increased pulse, BP unaffected or slight

Conjunctival reddening No effect on pupil size, resp. rate, DTRs Initial euphoria then relaxation Appetite stimulation Slowed reaction time, altered

perception, impaired coordination May cause paranoia, delusions,

hallucinations, depersonalization

Inhaled Marijuana

has all (except one) the same chemical carcinogens found in tobacco

> 400 chemicals High tar content Respiratory epithelium damage Obstruction on PFTs COPD in chronic users H & N, lung cancer reports

What’s A Reasonable Dose Of Inhaled Marijuana For Symptom

Control? Bioavailability of THC in smoked marijuana

ranges from 10 – 27%; significantly influenced by technique/experience

Typical cannabis cigarette has a mass between 0.5 - 1 gm

Informal surveys in US of medicinal cannabis users indicate avg. use of 10 - 20 gm/wk, or 1.42 - 2.86 g/day

Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs 2004; 7(5):464-470.

http://palliative.info

College of Physicians & Surgeons of MB

Oct. 2001 Newsletter

“Physicians who recommend, support the use of, or

prescribe this substance, must be fully

knowledgeable of the risks, benefits, potential

complications, and drug interactions associated

with its use. Based on the available scientific

evidence, the medicinal use of smoked marijuana is

at present generally without valid scientific

foundation and physicians should not feel obliged to

recommend, support, or prescribe this substance”

Oral Cannabinoids

∆9-tetrahydrocannabinol (THC; Marinol; Dronabinol)

Nabilone – synthetic derivative of THC

90 – 95% absorbed, but only 10 – 20% reaches circulation due to hepatic first-pass metabolism

1 hr to peak effect vs. 15 min. if smoked

Available Cannabinoids

Sources: Provincial Drug List; CPS 2002; Marihuana Medical Access Regulations (MMAR), April 2001, Health Canada

Available cannabinoids: Pharmacokinetics

Sources: Néron A, Le medecin du Québec 2001; Product monograph NCesamet ICN Canada 2002; Product monograph NMarinol Sanofi-Synthelabo 2002

Management of Bone Pain

Pharmacologic treatment

Acetaminophen Opioids NSAIDs – be aware of adverse effects! Corticosteroids (not with NSAIDS) Bisphosphonates: pamidronate

(Aredia), clodronate (Bonefos), zoledronate (Zometa)

Bisphosphonates

Osteoclast inhibitors bone metastases: pooled results signif. in all

skeletal morbidity end points except spinal cord compression

signif. time to first skeletal related event, suggesting they should be started when bone metastases are diagnosed

skeletal morbidity and should be continued until no longer clinically relevant

do not affect survival Most evidence supports use of IV

aminobisphosphonates, but further studies needed to determine best drug & route

Ross et al;Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327(7413):469

BisphosphonatesTolerability And Adverse Effects

1. Renal toxicity

2. Flu-like syndrome

3. Hypocalcemia

4. Avascular necrosis of the jaw

BisphosphonatesRenal Implications

Renal toxicity – IV bisphosphonates In rare cases can be life-threatening 9% of patients receiving 4 mg zoledronate and

8% of those receiving 90 mg pamidronate with normal baseline renal function developed increased creatinine levels (Rosen et al; J Clin Oncol 2003)

Should monitor creatinine before each dose, and hold repeat dosing until within 10% of baseline

Make sure patient is well hydrated prior to administration (eg. in hypercalcemia)

Bisphosphonates ctd

Flu-Like Reaction Esp. with intravenous bisphosphonates Up to 36% of patients Usually managed with acetaminophen

Hypocalcemia Usually compensate by increased PTH secretion Hypomagnesemia, previous parathyroid removal,

Vit D deficiency are risk factors Recommendations are to give 500 mg Calcium

and 400 IU Vit. D as daily supplements

BisphosphonatesAvascular Necrosis of Jaw

Robinson NA, Yeo JF. Bisphosphonates--a word of caution. Ann Acad Med Singapore 2004; 33(4 Suppl):48-49.

Greenberg MS. Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98(3):259-260.

Schwartz HC. Osteonecrosis and bisphosphonates: correlation versus causation. J Oral Maxillofac Surg 2004; 62(6):763-764.

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62(5):527-534.

Pogrel MA. Bisphosphonates and bone necrosis. J Oral Maxillofac Surg 2004; 62(3):391-392. Carter GD, Goss AN. Bisphosphonates and avascular necrosis of the jaws. Aust Dent J 2003;

48(4):268. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003;

21(22):4253-4254. Tarassoff P, Csermak K. Avascular necrosis of the jaws: risk factors in metastatic cancer

patients. J Oral Maxillofac Surg 2003; 61(10):1238-1239. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the

jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61(9):1115-1117.

BisphosphonatesAvascular Necrosis of Jaw ctd

Retrospective chart review Feb. 2001 – Nov. 2003

63 patients with chronic osteonecrosis of jaw while on bisphosphonates; 7 for osteoporosis

4 patients during that time period with similar presentation while not on bisphosphonates; 3 of them had prior local radiation for sq. cell CA

Localized vascular insufficiency, similar to osteoradionecrosis

Correlation with dental procedures - suggest a complete dental exam prior to long-term bisphosphonate treatment, and any dental pathology addressed

Adjuvants in

Neuropathic Pain

Gabapentin

a second line anticonvulsant shown to be effective in neuropathic pain;

has become a first-line agent in neuropathic pain

structural analog of GABA, but does not bind to GABA receptors

increases concentration and synthesis of GABA in the brain

GABA receptors have been shown to mediate pre- and postsynaptic inhibition in sensory afferent fibers

Gabapentin

Common Starting Regimen 300 mg hs Day 1, 300 mg bid

Day2, 300 mg tid Day 3, then gradually titrate to effect up to 1200 mg tid

Frail patients 100 mg hs Day 1, 100 mg bid Day

2, 100 mg tid Day 3, then gradually titrate to effect

TCAs

increase in monoamine activity in descending pain modulating pathways

inhibition of reuptake of NE and serotonin at spinal dorsal horn synapses

alt. mechanisms include blockade of Na+ channels, GABA effects, K+ channel blockade, adenosine

neuropathic pain, esp. continuous dysaesthesia anticholinergic adverse effects; amitriptyline >

nortriptyline > desipramine lower doses and earlier response than

depression

SSRIs And Newer Antidepressants

less convincing evidence for independent analgesic effects; those affecting both noradrenaline and serotonin levels have more potent and efficacious antinociceptive effects than SSRIs

newer meds with mixed neurotransmitter effects:1. Serotonin and Noradrenergic Reuptake Inhibitors

(SNaRI) – eg. Venlafaxine (Effexor), nefazodone (Serzone), duloxetine

2. Noradrenergic and Specific Serotoninergic Antidepressants (NaSSA) – eg. mirtazapine (Remeron)

3. Noradrenaline Reuptake Inhibitors (NaRI) – eg. reboxetine

Topiramate

Multiple neurostabilizing actions: anti-glutamate effects at AMPA receptors;

blockade of voltage activated Na+ channels; enhancement of GABA-mediated neuroinhibition; inhibition of L-type high voltage-activated Ca++ currents; activation of potassium conductance

Neuropathic Pain Consider if gabapentin failed Typically start with 25 mg/day Effectiveness demonstrated in diabetic neuropathy Ocular adverse effects include secondary angle-

closure glaucoma, transient myopia, and uveal effusions

Decreased serum bicarbonate in up to 67%

Ketamine Disassociative anesthetic Analgesic in subanesthetic doses Most potent NMDA receptor antagonist available

for clinical use NMDA-receptor activation is associated with

windup, hyperalgesia and reduced opioid sensitivity.

Ketamine is widely used in cancer pain to improve opioid analgesia when tolerance has developed or the pain is considered to be opioid resistant.

Randomised and controlled trials are rare; data from two of these trials suggest potential benefit of ketamine as adjuvant to morphine in cancer pain (Bell et al., 2003).

Ketamine

Often use oral dosing of intravenous preparation

A common starting dose is 10 mg qid po (low dose)

Concomitant benzodiazepine administration may attenuate adverse CNS effects (eg. Lorazepam 0.5 – 1 mg sl bid – tid)

Decrease concurrent opioid dose by 25 – 50%

Clonidine

alpha-2 agonist decrease sympathetic transmitter release

through pre and post-synaptic inhibition Considered in refractory neuropathic pain Literature predominantly regarding spinal

administration Recent literature suggests possible

topical role

Calcitonin

Osteoclast inhibition Cochrane review 2003: “The limited

evidence currently available for systematic review does not support the use of calcitonin to control pain from bone metastases. Until new studies provide additional information on this treatment, other therapeutic approaches should be considered ”

Case Presentation ctd

Rule out opioid-induced neurotoxicity d/c NSAID Add gabapentin and dexamethasone Consider:

CT to determine anatomy; ? Radiation Methadone Ketamine TCA Topiramate Spinal analgesia

Opioid-Induced Neurotoxicity (OIN)

Potentially fatal neuropsychiatric syndrome of:

Cognitive dysfunction Delirium Hallucinations Myoclonus/seizures Hyperalgesia / allodynia

Increasing incidence – practitioners more comfortable and aggressive with opioids

NMDA receptor involved Early recognition is critical

Seizures,Death

Opioidtolerance

Mild myoclonus(eg. with sleeping)

Severe myoclonus

Delirium

Agitation

Misinterpretedas Pain

OpioidsIncreased

Hyperalgesia

Misinterpretedas Disease-Related Pain

OpioidsIncreased

Spectrum of Opioid-Induced Neurotoxicity

OIN: Recognition

Myoclonus – twitching of large muscle

groups

Delirium

Rapidly escalating dose requirement

Pain “doesn’t make sense”; not

consistent with recent pattern or known

disease

OIN: Treatment

Switch opioid (rotation) or reduce opioid dose; usually much lower than expected doses of alternate opioid required… often use prn initially

Hydration

Benzodiazepines for neuromuscular excitation