Palliative Pain
Control… the Role
of Adjuvant
Treatments
Dr. Nathalie Slaney, BScN, MD, CCFP
Maison Vale Hospice Physician/Shared Care Team Lead
Physician
Conflict of Interest
Declaration
• I have no financial or personal relationships to
disclose…
• As a Palliative Care Advisory Committee
Member, I was asked to present. I have been
reimbursed for my expenses (hotel room +
gas)
George
• 64 yr old man with advanced rheumatoid
arthritis – diagnosed at age 12yrs. He was
dependent on high doses of steroids most of
his life. He is wheelchair dependent and has
severe joint deformity as a result of RA and
severe osteoporosis. Most vertebrae are
collapsed. Developed psoriatric arthritis.
• He is unable to eat, due to TMJ and cervical
spine destruction- lives on 3-4 ensures per day.
Must eat reclined. Lives in wheelchair- huge,
painful sacral ulcer
• Pain 8-9/10
• Mainly bone pain, but also joint pain from the
severe hand/feet deformities
• Experiencing neck and back spasms from the
compression fractures
• Sharp, shooting neuropathic pain down both
arms
• Ulcer- causes significant discomfort
• Current meds:
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Celexa 40 mg daily
Celebrex 200 mg po daily
Diazepam 10mg po daily
Fentanyl patch 275 mcg Q2 days
Tylenol #4- 1 to 2 tabs Q3h (takes this regularly)
Dilaudid 8 mg po Q3h PRN (uses Q3h)
Zopiclone 7.5 mg- 1-1/2 tabs every night
Lansoprazole 30 mg po BID
When what we usually
do is not enough…
• Where do we go from here?
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Fentanyl 275 + Tylenol #4 (16) + Dilaudid 8mg (16)
(275x3.6=990)+(960mgx0.15=144)+(128x5=640)
Taking equivalent of 1,774 mg of oral morphine daily
Diazepam for spasms, celebrex, & 5,200 mg
acetominophen
• What types of pain is George experiencing?
• What changes, if any would we do?
Adjuvant Therapy
• Most adjuvant analgesics have different mechanisms
of action and complement the activity of opioid
analgesics
• They can interfere with perception or transmission
of pain signals at the spinal, supraspinal, or
peripheral level and help alleviate nociceptive and
neuropathic pain
• Objective of adjuvant therapy is to complement and
optimize opioids and to prevent complications from
poor pain control
What to chose… and
when to chose it
• Choice based on type of pain being treated
• Most patients with cancer experience nociceptive
pain and neuropathic pain
• Regardless of the adjuvant chosen and it’s
indication:
• Try use one at a time to avoid problems caused by
polypharmacy
• Start low, go slow (ie: q2-5 days, until good effect
or adverse effects or max dose reached)
• Opioid doses MUST be reassessed when
starting adjuvant therapy (watch for signs of
overdose)
• Pts with neuropathic pain are at risk because
they are typically receiving fairly high doses of
opioids when they start taking adjuvants
• Occasionally, we have to combine more than
one analgesia adjuvant – even though there is
little evidence to support this, its often helpful
• Bone pain: (nociceptive pain)
• First line: NSAIDS- effective 75% pts
• Steroids (if contraindications to NSAIDs) or combo*
• Think GI protection if use both
• Biphosphonates (pamidronate, zoledronate)especially good for hypercalcemia from cancer.
Indicated for breast ca/MM
• Usually 15-30% relief on scale and slow onset of action
• Most common side effect- flu like symptoms
• Radiation (takes ~3wks, lasts 4-12 mo)
• Calcitonin- withdrawn from market 2013
• Non pharm: Rx, Sx (fixation), orthotic device,
walker, cane, crutches
• Massage, relaxation/guided imagery, wax
treatments, Reiki
• Neuropathic pain:
• generally does not respond well to opioids
• First line:
• Topical agents (capsaicin)
• Compound cream Rx: lidocaine 10%, ketamine 5%,
and clonidine 0.2%. 100ml. Apply QID
• TCA (amitriptylline, desipramine) useful when
insomnia and depression- but anticholinergic SE
• Gabapentin, pregabalin (*Gaba= interaction with
antacids). SE: drowsiness, dizziness, difficulty
concentrating (better 2-4wks)
• If SE unbearable, taper every 2-3 days. If can’t do
this slowly, cover with benzo
• Steroids
• Act centrally as well as peripherally
• Anti-inflammatory effects reduces peri-tumoural
edema and relieves compression and distention
• They also improve the response of neuropathic
pain to opioids
• Most common agent is dexamethasone (po,s/c)
• When good effect, lower dose gradually to the
minimum effective dose so there are less long
term effects
• Second line: serotonin and norepinephrine
reuptake inhibitors
• Venlafaxine (marketed in Canada as Effexor)
• Start at 37.5 mg OD-BID, titrate by 37.5-75mg
every week to max of 225mg per day
• A trial of 4-6 wks at dose of at least 150mg/day is
necessary to access its benefits
• Duloxetine (marketed in Canada as Cymbalta)
• Usual starting dose is 30 mg, can increase to
60mg. Higher doses not shown additional benefit
• A trial of 4 weeks at max dose considered
adequate
• Third line- tramadol and the opioids
• Start 50-100 mg Q4-6h (no more than 400mg/day)
• Tramadol ER: start 100mg OD and titrate up PRN by
100mg increments Q5days to max 300mg/day
• Fourth line: SSRIs (selective serotonin reuptake inhib)
• Citalopram
• Paroxetine
• Or norepinephrine and dopamine reuptake inhibitor
(buproprion), noradrenergic and serotoninergic
antidepressant (mirtazapine), or other anticonvusants
• Ketamine:
• Test dose: one dose of 5-20mg s/c (most ppl
require 10mg) can help determine efficacy/ SE
• Initial daily dose: 40-150mg/day, increase slowly
and gradually or 0.1mg/kg per hour by
continuous infusion or divided into 4-6
injections per day. 40-60mg per day often
enough
• Onset of action (s/c) is 15-30 minutes. Po: 30 min
• PO:SC dose variable ! 33-100% of SC dose
• Injectable solution can be given orally, but very
bitter
• Contraindications:
• relative: HTN, Heart failure, hx of CVD, ICP, Seizures,
neurological damage
• Absolute: hypersensitivity, stroke
• Adverse effects: euphoria (haldol or lorazepam), for
bronchial hypersecretions (glyco 0.2mg S.c Q2H prn)
• For pain, induration: change infusion site. Conc.?
cannabinoids
• Nabilone (cesamet) start with 0.25-0.5 mg po QHS, increase
by increments of 0.25-1mg/day every 3-7 days to max of 2
mg po BID or TID
• Dose adjustment can be done in syrup made at 0.5mg/5ml
• Dronabinol (marinol) begin with 2.5mg po QHS, increase by
2.5mg every 3-7 days to max of 20mg /day in divided doses
• Tetrahydrocannabinol-cannabidiol (sativex) 4-12 sprays/day
on average, given bucally or s/l. allow at least 30 minutes
between sprays
• *caution when using cannabinoids with CVD or mental
health disorders !
Other agents…
• Methotrimeprazine (nozinan) 5mg po or SC BID to
25 mg QID to max of 300mg per day. Increase by
5-10mg/day until relief achieved or adverse effects
• Baclofen for spasms or hiccups: 5mg-20 mg po TID
(start with 5mg TID and increase by 5TID every 3
days to max of 80mg/day
• Diazepam 2mg po TID x 2 days, then 5mg TID to
10mg TID
• Buscopan for abdo cramps (hyoscine
butylbromide) 10-20 mg po or SC Q6-8 h up to
120mg/day
• Methadone:
• For wounds: methadone powder 100mg in 1
stomadhesive powder for dressing change up to
BID
• For pain:
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Oral absorption: rapid and almost complete
Oral bioavailability 80%
Sublingual absorption 34%
Ratio of oral to rectal dosage 1:1
Onset 30minutes
Peak activity: 2.5-4 hours
Time to reach steady state: 5 days!
• Switching to methadone:
• Calculate morphine oral equivalent
• Calculate the equivalent methadone dose using a 10:1
ratio of oral morphine to oral meth
• Day 1- reduce daily dose of initial opioid by 1/3 + give 1/3
calculated meth dose, with 1/3 of this amount given every
8 hours. Use initial opioid for BT
• Day 2- reduce daily dose of initial opioid by another 1/3 if
pt has mod to severe pain. Use initial opioid for BT
• Day 3- stop initial opioid. Increase meth dose by another
1/3 if pt has mod to severe pain. Once dose adjustment
complete and regular methadone dose stable, use meth
at 10% daily dose every our for PRN BT
Methylnaltrexone for opioidinduced constipation
• Approved by Health Canada in 2008 for treatment of opioidinduced constipation in patients with advanced illness,
receiving palliative care.
• Relistor should be used as an adjunct therapy to induce a
prompt bowel movement when the response to laxative
therapy is not sufficient
• It contains the medicinal ingredient methylnaltrexone
bromide which is a selective, peripherally acting µ-opioid
receptor antagonist
• It treats OIC by blocking the constipating effects of opioids in
the gastrointestinal tract without crossing the blood-brain
barrier and interfering with the analgesic effects of opioids.
• Neither opioid withdrawal syndrome nor
changes in pain scores were consistently
shown in the Relistor treatment group
• No need to increase opioid dosages
• Relistor is not indicated for use in children and
adolescents
Does it work? Where’s
the proof?
• efficacy and safety of Relistor was evaluated in two double
blind, placebo controlled trials in patients receiving
palliative care: a single dose trial, and a multiple dose trial.
• Relistor subcutaneous administration resulted in a higher
proportion of patients with rescue-free laxation within 4
hours as compared to placebo treated patients
• In addition the proportion of patients who had a laxation
response within 4 hours after at least 2 of the first 4 doses
(the first week of treatment) was also higher in the Relistor
than in the placebo group.
• There was no difference in the efficacy or safety profile in
elderly patients when compared to younger patients.
Like-minded Neighbors..
• FDA also approved Methylnaltrexone in 2008 for
same indication
• In 2012, Salix/Progenics Pharmaceuticals
submitted application for the treatment of opioidinduced constipation (OIC) in patients taking
opioids for noncancer pain. This was declined in
July, pending more supporting data
• After a review of data, approval was granted In
September 2014 for new indication
Supporting data
• Approval based on results of a randomized,
double-blind, placebo-controlled trial including
a total of 312 patients with a history of non
cancer pain who were taking opioids for at
least 1 month prior to study entry.
• All had confirmed constipation, defined as less
than 3 spontaneous bowel movements per
week during the screening period.
• Constipation due to opioid use had to be
associated with 1 of more of the following:
• a Bristol Stool Form Scale score of 1 or 2 for at
least 25% of the bowel movements;
• straining during, or a sensation of incomplete
evacuation after at least 25% of the bowel
movements.
• The median duration of constipation at
baseline was 59 months
• The median daily baseline oral morphine
equivalent dose was 161 mg
• Patients were randomized to receive
methylnaltrexone 12 mg or placebo once daily
for 4 weeks, followed by an 8 week open-label
phase where patients could take medications
as needed
• Study results showed that a significantly
important proportion of patients taking
methylnaltrexone reported having 3 or more
spontaneous bowel movements during the 4week double-blind period vs placebo (59% vs 38%)
• After the first dose, 33% of treated patients
reported having a spontaneous bowel movement
within 4 hours, and approximately 50% had a
bowel movement prior to the second dose.
• Treatment was well tolerated, and adverse events
were consistent with those seen with other studies
of the drug in an advanced illness population
• The use of the drug beyond 4 months has not been
studied in the advanced illness population
• The most common side effects were abdominal
pain (21%), diarrhea (6%), nausea (9%), and
hyperhidrosis (6%).
• Hot flush, tremor, and chills were also seen.
How is it given?
• Methylnaltrexone bromide sold as Relistor (20 mg/ml).
Usual dose is 12 mg (0.6ml)
• Administered S/C in the upper arm, abdomen or thigh.
• Patients should be seated or recumbent during dosing
and care should be taken when the patient stands
following dosing.
• Injections should be administered every other day, as
needed. Physicians should consider discontinuing
treatment in patients who fail to show an adequate
response after 4 doses (1 week).
When NOT to use it…
• contraindicated in patients with known or
suspected mechanical gastrointestinal obstruction
or acute surgical abdomen and in patients who are
hypersensitive to Relistor or any of its components.
• Cases of perforation have been reported in patients
with advanced illness in conditions that may be
associated with localized or diffuse reduction in the
structural integrity of the GI tract, such as peptic
ulcer disease, Ogilvie syndrome, diverticular
disease, infiltrative GI tract malignancies, or
peritoneal metastases
• It should not be used for treatment of patients
with constipation not related to opioid use.
• Patients with severe renal impairment should
receive half of the recommended dose
• Monitor for the development of severe,
persistent, or worsening abdominal pain;
discontinue Relistor in patients who develop
this symptom.
• Patients generally experience a rapid bowel
movement following administration of
methylnaltrexone, often within 30 minutes
• most patients describe the sensation like a
normal bowel activity
• Problem: like everything else… money. Only
some third party coverage. $50-80 an injection
• Thank you for your time, and your patience…
• And thank you for the great work you do.
• Questions? Comments?