1. Palliative Pain Control… the Role of Adjuvant Treatments
Dr. Nathalie Slaney, BScN, MD, CCFP
Maison Vale Hospice Physician/Shared Care Team Lead Physician

2. 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)

3. 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

4. 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

5. Current meds: 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

6. When what we usually do is not enough…
Where do we go from here?
Fentanyl 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?

7. 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

8. 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)

9. 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

10. 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

11. Non pharm: Rx, Sx (fixation), orthotic device, walker, cane, crutches
Massage, relaxation/guided imagery, wax treatments, Reiki

12. 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

13. 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

14. Second line: serotonin and norepinephrine reuptake inhibitors
Venlafaxine (marketed in Canada as Effexor)
Start at 37.5 mg OD-BID, titrate by mg 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
Nausea *

15. Third line- tramadol and the opioids
Start 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

16. Ketamine:
Test dose: one dose of 5-20mg s/c (most ppl require 10mg) can help determine efficacy/ SE
Initial daily dose: mg/day, increase slowly and gradually or 0.1mg/kg per hour by continuous infusion or divided into 4-6 injections per day mg per day often enough
Onset of action (s/c) is minutes. Po: 30 min

17. 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.?

18. cannabinoids
Nabilone (cesamet) start with mg po QHS, increase by increments of mg/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 !

19. 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) mg po or SC Q6-8 h up to 120mg/day

20. Methadone:
For wounds: methadone powder 100mg in 1 stomadhesive powder for dressing change up to BID
For pain:
Oral absorption: rapid and almost complete
Oral bioavailability 80%
Sublingual absorption 34%
Ratio of oral to rectal dosage 1:1
Onset 30minutes
Peak activity: hours
Time to reach steady state: 5 days!

21. 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

22. Methylnaltrexone for opioid-induced constipation
Approved by Health Canada in 2008 for treatment of opioid- induced 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.
is a selective antagonist of opioid binding at the μ-opioid receptor

23. 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

24. 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.

25. Like-minded Neighbors..
FDA also approved Methylnaltrexone in 2008 for same indication
In 2012, Salix/Progenics Pharmaceuticals submitted application for the treatment of opioid- induced 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

26. 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.

27. 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.

29. 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

30. Study results showed that a significantly important proportion of patients taking methylnaltrexone reported having 3 or more spontaneous bowel movements during the 4- week 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.

31. 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.

32. 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).

33. 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

34. 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.

35. 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

36. Thank you for your time, and your patience…
And thank you for the great work you do.
Questions? Comments?