1. Tapering strong opioids
Dr. Eldon Tunks
Tapering strong opioids

2. Faculty/Presenter Disclosure
Faculty: Dr. Eldon Tunks
Relationships with commercial interests
In past 2 years 3 honoraria from Purdue for giving a talk on depression, and one from Paladin for answering a questionnaire

3. Learning objectives for this presentation
This presentation addresses competencies for medical expert: Assessing the mechanism of pain problem, choosing the treatment that may relieve the mechanisms identified, choosing the tapering strategies relevant to excessive dosage, dependency, adverse effect of opioid, safe use, and long-term efficacy: The objectives are to
Increase expertise in identifying the mechanisms and comorbidities, and risk-benefits in order to choose or recommend the changes
Choose a concrete plan for management of the pain and withdrawal symptoms, while providing pharmacological and behavioural support
opioid substitution strategies; Choose a concrete plan to safely rotate from strong opioid to methadone, or strong opioid to partial agonist and/or adjuvants
The learner will have ability to educate and recommend to patient appropriate opioid rotation strategies and institute or supervise the rotation

4. Changes induced by continued strong opioid administration
Tolerance sets in: mechanisms include
phosphorylation of the opioid receptor,
neuromodulation by Beta-arrestin attaching to the receptor
endocytosis (internalization) – receptor disappears from surface of the cell membrane and is reassembled intracellularly where it is not accessible to opioid
Williams et al. Regulation of mu opioid receptors. Pharmacological reviews, (2013) 65:

5. Changes induced by continued strong opioid administration
Paradoxical pain (opioid -induced hyperalgesia) may result. Opioid receptors connecting downstream to chloride channels that are common pathway for multiple depressants including alcohol, barbiturates, benzodiazepines, GABA. The active transport of chloride in the chloride channel may be impaired with prolonged opioid administration resulting in paradoxical depolarization of the membrane and increased pain, (increased agitation in the case of benzodiazepine or alcohol receptors)
TJ Price, SA Prescott·Pain. 156 (2015)

6. Eventual toxicity to strong opioid, requiring tapering
Respiratory (desaturation, apnea)
Gastrointestinal (nausea/vomiting, biliary spasm, constipation, narcotic bowel)
Urinary retention
Sweating
Dysphoria
Dependence or abuse
Neurological (seizure, myoclonus)
Hypogonadism, menstrual irregularity, erectile dysfunction, gynecomastia
Cognitive (confusion, slow reaction time)
arrhythmia; QTc lengthening
Bradycardia, shock
Paradoxical sensitization to pain
Withdrawal syndromes even while still taking the opioid (due to tolerance)
Itch; histamine release or central effect
Drug interactions – eg. benzodiazepine

7. Tapering strategies
The common a strategy is to slowly withdraw the strong opioid in proportions between 5% to 10% every 2-4 weeks
managing autonomic responses to opioid withdrawal
sweating: low dose clonidine 0.1 to mg TID PRN
nausea /vomiting: nabilone or medical cannabis , domperidone, metoclopramide
agitation and insomnia: Short-term use of low dose lorazepam or clonazepam, one to two weeks, with supervision
Note warnings about combined use of benzodiazepine with opioid

8. Opioid with benzodiazepine-guideline issues
Most opioid guidelines recommend against the coadministration of benzodiazepine and opioid.
Sometimes limited combined use is not avoidable
when patients have already been taking benzodiazepine prolonged time,
when benzodiazepines are needed in low dose to deal with short-term acute opioid withdrawal symptoms,
in some psychiatric cases such as phobias or agoraphobia.
When there is spasticity requiring pharmacological intervention

9. When considering opioid combined with benzodiazepine
Avoid benzodiazepine when history of paradoxical agitation, COPD, history of benzodiazepine or alcohol dependency or overdose, history of accidental overdose or ER intervention
Generally weaning long term high dose benzodiazepines must be done very carefully over several weeks or months, and sometimes over 6 months or a year.
For acute opioid withdrawal they may be used in low doses for one or two weeks in which case the patient should be followed closely and advised to reduce or stop the benzodiazepine if there is drowsiness or impairment

10. Hoped-for results of opioid tapering
One would expect that lowering the opioid dose or discontinuing would eliminate the risks,
that tolerance would be reversed resulting in better pain relief with less medication,
and that opioid-induced paradoxical pain would be reversed.
These favorable results may often occur, but there are some exceptions requiring refinement of strategies

11. Many patients are able to reduce or taper strong opioids voluntarily and gradually and without distress or impaired functions
Others resist even the idea of tapering, and on tapering efforts call the physician with complaints of intolerable pain and poor function

12. Complication of emotional factors
Some patients associate the pain and opioid use experience with fear of loss of control of pain, and fear of abandonment by the prescribers, and fear of harm from treatment or from actions suggested to alter or change the opioid prescriptions
These factors may be termed somatization, kinesiophobia, catastrophizing, but all imply anxiety about loss of control over pain

13. Helping the fearful to taper
Psychoeducation: explaining the “side effects and long range adverse effects” and better probability of improvement with tapering
Anxiety coping skills: applied relaxation, taught and practiced before taking on tapering
Changing long acting to short acting: this gives a better impression of pain responsiveness despite tapering
Interventional and trigger point blocks: improving the confidence that pain improvements are still possible
Rotation from strong opioid to partial agonists, gabapentinoid, relaxants and other options, providing more relief of hyperalgesic pains

14. Multidisciplinary programs as an alternative to strong opioid
Multidisciplinary and behavioural treatments, initially proposed by Fordyce in 1969, have been effective in improving quality of life, adjustment, coping, and self-management strategies for people suffering pain. However, pain relief is not usually a byproduct of such treatment.
Access to such programs also is limited, funding is only occasionally available, they are often located in large urban centres, and have long waiting lists, and cannot possibly service the bulk of the patients who suffer pain.

15. Unrelieved pain
One must not lose sight of the fact that a substantial proportion of the population suffer significant constant or intermittent pains – 15 to 20%. This should be taken into account in plans to taper or discontinue strong opioid.
Although in some cases pain itself can be perpetuated or aggravated by ongoing strong opioid as a paradoxical reaction, pain relief resulting from tapering occurs only in a minority. Multiple other pain mechanisms exist (especially neuropathic and hyperalgesic disorders) and pain often introduces patients to misuse of analgesics

16. The broader issues in tapering
What to do with the original pain?
How to manage those with significant drug dependency, misuse, and addiction?
If simple gradual tapering proves not successful, what other alternatives might aid tapering?

17. When strong opioids may not be appropriate
However, many chronic pain conditions (Fibromyalgia, chronic daily headache, post-stroke neuralgia, opioid induced hyperalgesia, chronic widespread hyperalgesias, denervation dysesthesias, post Guillain-Barre syndrome, chronic functional bowel pain, small fiber neuropathy etc.) do not respond well to strong opioid.
These mechanisms may respond better to some anticonvulsants, gabapentinoids, sodium channel blockers, interventional procedures, partial opioid agonists or opioid partial agonist-antagonists, SNRI, interventional treatment etc.

18. The problem with the WHO analgesic ladder
WHO analgesic ladder assumes that pain should be addressed first with the least toxic and non- opioid analgesics such as acetaminophen, graduating to NSAID, and finally to strong opioid. Modern guidelines have added that before considering pharmacological methods, one should consider nonpharmacological, medical or behavioural treatments

19. neuralgias
In analgesic failure, one should reassess the patient and identify pain mechanisms and match to treatment mechanisms.
For example for neuralgia with paroxysmal pain associated with clinical evidence of injury to myelinated fibers, sodium channel blockers (lamotrigine, buprenorphine or carbamazepine would be more likely to be effective), compared to gabapentinoids or strong opioids for example

20. hyperalgesias
Hyperalgesias (characterized by tenderness, persistent pain, allodynia, punctate hyperalgesia) are more likely to respond to gabapentinoids, tramadol, tapentadol, SNRI, TCAs. baclofen or tizanidine
Injected Botox, topical lidocaine, infusions
Trigger point blocks, interventional procedures
Applied relaxation

21. Denervation hyperalgesias, post-stroke neuralgias, small fiber neuropathies, chronic ischemic pain
Combinations:
duloxetine
Buprenorphine
TCA
Antidepressant for coexisting depression
Applied relaxation

22. Opioid substitution for opioid dependency/addiction, Methadone
Methadone has lower relapse rate and is a stronger mu agonist analgesic.
It is easier to find a methadone clinic and the services are funded
Rotating off strong opioids to Buprenorphine/naloxone is more unpleasant with more withdrawal than one would experience with rotation to methadone
Methadone does not resolve the problems of opioid induced hyperalgesia, craving, potential for concurrent abuse of opioid with methadone

23. Opioid partial agonist-antagonist substitution; Buprenorphine/naloxone
buprenorphine/naloxone (buprenorphine/naloxone) is more effective for hyperalgesia, opioid induced hyperalgesia, polydrug abuse involving substances other than opioid
Since October 2016, the restriction is now removed for physicians to take a course and get a diploma in order to prescribe, but funding is still limited

24. Opioid partial agonist-antagonist substitution (cont’d)
There is potential for stabilizing a patient on buprenorphine/naloxone and then rotating the dose downward and rotating to transdermal buprenorphine for maintenance if private insurance funding exists.
It is easier to rotate patients from strong mu agonist opioid to buprenorphine/naloxone, but quite difficult if the patient takes high dose of oxycodone
(In 2018, Belbuca will be introduced in Canada; transmucosal buprenorphine on-label for pain.)

25. Rotation between kappa and mu agonists for tapering
If a patient has become tolerant to a high dose mu agonist but not oxycodone (kappa agonist), it may be possible to introduce oxycodone at one quarter or one half the calculated morphine equivalent dose as the mu agonist is rotated down while replacing with the kappa agonist

26. Rotation between kappa and mu agonists (cont’d)
It is harder to replace the kappa agonist with the mu agonist and very difficult to rotate from kappa agonist (Oxycodone) dependency to Buprenorphine directly
A strategy for resolving high-dose oxycodone dependency is to gradually rotate oxycodone to methadone over several weeks and then use Buprenorphine/naloxone to rotate off methadone over about one week

27. Example of protocol for introducing Buprenorphine/naloxone
In a patient already using a strong opioid agonist
The evening before starting Buprenorphine, reduce strong opioid by 25%, to provoke beginning of abstinence syndrome by next AM
12 hours later, begin Buprenorphine/naloxone 2/0.5 mg 1 tab qAM and 1 qPM, for day 1 and 2

28. Rapid rotation from strong opioid: Acute withdrawal phase
Next 2 days, Buprenorphine/naloxone 2 mg tid, up to 4 mg BID for two days
Next 2 days, Buprenorphine/naloxone dose reviewed and continued 2 mg tid, up to 4 BID or up to 8 mg TID
Accompanied by clonidine 0.05 – 0.1 mg tid prn and clonazepam mg tid 0r lorazepam 0.5 mg TID PRN: if there is drowsiness or cognitive impairment, reduce or stop Benzodiazepine but continue the clonidine PRN for one to 2 weeks until the withdrawal symptoms are resolved (note comment next slide)

29. Rapid rotation from strong opioid
Reducing strong opioid by ¼ of original dose every 2 days until discontinued Or
Reducing original strong opioid first 2 days to 50%, next two days 25%, next two days 10%, and day seven discontinue

30. Supportive therapy during withdrawal
the withdrawal symptoms resolve usually by 7 to 10 days
During this time low dose benzodiazepine (if tolerated and not contraindicated) with clonidine will significantly mute the unpleasant autonomic/psychological distress
Applied relaxation taught and practiced with the patient before the rotation gives the patient an increased measure of control

31. Using tramadol to assist weaning strong opioid
Pains often become chronic due to the addition of hyperalgesic mechanisms or due to neuralgia.
Strong opioids are not particularly effective for hyperalgesias and neuralgias, and in a minority of cases Opioids may even aggravate them
Tramadol is a partial Opioid agonist that is more effective in hyperalgesic or neuralgia conditions

32. Tramadol versus tapentadol
Tapentadol is also a partial opioid agonist with greater mu agonist affinity and stronger adrenergic than serotonergic effect. It also appears to have efficacy for hyperalgesic states.
Although Dart et al reported in Pain Medicine (2016) 17: that there is less diversion risk with tapentadol, the data was based on soft data. At most one can say that tapentadol and tramadol both have a relatively lower affinity for the mu receptor, exert most of their effect through glial cells, and coadministration of naloxone has minimal effect on the analgesia. Tramadol or tapentadol can be abused but experience is that they are more effective for hyperalgesic and neuropathic conditions, compared to strong opioid

33. note there is a recent Health Canada warning February 22, regarding tramadol that it should be avoided in those under 18 or over 75, and it poses a possible risk for super metabolizers who may have a much stronger mu agonist effect than expected
Also try to limit coadministration of benzodiazepine or alcohol, with tramadol, tapentadol or buprenorphine: these increase the risk of toxicity

34. Using tramadol to assist weaning strong opioid
A strategy in these hyperalgesic or neuralgia conditions is to add tramadol to the existing analgesic, titrate tramadol to obtain improved control of hyperalgesia, then gradually reduce the strong opioid, leaving the tramadol as main analgesic

35. Usually tapering is not enough
Keep in mind that in any of these opioid tapering or rotations, psychosocial support, behavioural input, counseling, treatment of depression, are all important ingredients and without them there will not be success.