7.9 (9.7) Adjuvant analgesics Flashcards
What is an adjuvant analgesic?
What are 3 clinical situations in which they can be used (if patient already on primary analgesic)
A medication with a primary indication other than pain but is useful as a coanalgesic during opioid therapy.
- Combine with primary analgesic to enhance pain relief
- Treat pain that is refractory to the analgesic
- Allow reduction in the opioid dose (to limit adverse side effects)
Combine, replace, reduce
List 4 ways to limit polypharmacy when using adjuvant analgesics
- Consider adjuvant only after opioid response ascertained
- Sequential drug trials to identify an effective drug. Initiate at low dose with gradual titration
- Only one drug added at a time
- Ineffective drugs should be stopped
FS:
- One drug at a time
- Sequential drug trial
- Optimize first drug before adding more drug
- Stop ineffective drugs
List 3 conventional pain etiologies benefiting from adjuvant analgesics
- Multipurpose
- Neuropathic pain
- Bone pain
- For pain/other symptoms in a bowel obstruction
Multipurpose adjuvant meds can be considered for diverse pain syndromes.
List 6 multipurpose adjuvant meds
- glucocorticoids
- alpha-2 adrenergic agonists
- cannabinoids
- topical therapies
- botulinum toxin
- neuroleptics
- NMDA inhibitors
FS:
1. Antidepressant (SNRI, TCA)
2. Anticonvulsant (gaba, lyrica)
3. NMDA antagonist (ketamine)
4. Na channel blocker (lidocaine)
5. Alpha 2 adrenergic agonist (clonidine, demedetomodine)
6. Steroids
7. CBD
When considering the use of an adjuvant analgesic a comprehensive assessment of the patient is required.
What are 3 elements of this assessment?
- Characteristics of the pain (LOPQRST)
- Impact of pain on function and quality of life
- Distinguish nociceptive or neuropathic pain
- Underlying etiology of pain
- Presence of associated factors (ie assess for total pain), including physical and psychological symptoms, functional impairments, psychiatric disorder, family or social disruption, financial problems, and spiritual or religious concerns, and their effects on quality of life.
FS:
LOPQRSTUV
DDX
Neuropathic vs nociceptive vs total pain
What three elements that make adjuvant analgesics less desirable than conventional analgesics such as opioids?
What is the implication of this for the use of adjuvant analgesics?
- Less efficacy- smaller proportion of treated patients who respond adequately
- Slower onset of analgesic effect (perhaps due to the need to initiate therapy at low doses to avoid side effects)
- More SEs
Most patients with moderate or severe pain related to serious medical illness should have opioids optimized FIRST before trying an adjuvant analgesic
What is sequential drug trial and why might this be required with adjuvant analgesia?
Sequential drug trials = only add 1 drug at a time, use low initial doses and gradual dose titration. Stop ineffective drugs
Why? Great patient variability in response to adjuvant analgesics and therefore inability to reliably predict the outcome of therapy
The process of sequential drug trials should be explained to the patient at the start of therapy to enhance adherence and reduce the distress that may occur as treatments fail.
Name six classes of adjuvant analgesics? Provide an example from each class
Table 7.9.1
Antidepressants- TCAs, SNRIs, SSRIs
Anticonvulsants- Gabapentin, pregabalin, topiramate, carbamazepine, phenytoin, valproate, oxcarbazepine, lamotrigine, levetiracetam
Alpha-2 adrenergic agonists - Clonidine, tizanidine, dexmedetomidone
Botulinum toxin - A, B
Cannabinoids - Tetrahydrocanninol (THC), nabilone, THC:cannabidiol mixture
Corticosteroids - Dex
N-methyl-D-aspartate receptor antagonists - Dextromethorphan, ketamine
Sodium channel blockers Mexiletine, tocainide, flecainide
Topical agents - Capsaicin, lidocaine patch, EMLA®
A. List 3 palliative symptoms for which RCTs support use of glucocorticoids.
B. A systematic review showed only weak evidence for analgesic efficacy of GCs - however clinical experience is positive. List 5 specific pain syndromes in which GCs seem helpful.
A. Anorexia, fatigue, nausea
B.
bone pain*
neuropathic pain*
pain from bowel/duct obstruction*
organ capsule expansion*
headache from raised ICP*
pain from lymphedema
target inflammation as 2ndary analgesia
- There is no data to inform choice of GC for pain. List 3 acceptable options.
- List 4 toxicities of GC.
- List 3 factors that increase the risk of GC associated toxicity
- Dexamethasone
Prednisone
Methylprednisone - Hyperglycemia
Myopathy
Osteoporosis
Psych disturbance (anxiety, psychosis) - Dose
Duration of therapy
Predisposing medical comorbidities
Antidepressants have been used as analgesics for decades. Can be considered for any type of chronic pain.
List 2 ways mood factors into considering antidepressants as an adjuvant for pain.
- Pain relief may be enhanced if there is positive mood effect
- But analgesia does not require mood change
- An early trial of antidepressant may be considered if comorbid depression
FS:
Improving mood = improving pain
Comorb depression
List 1 biological mechanism for how antidepressants (SNRI) may have analgesic effects
Enhanced availability of monoamines at synapses within descending pain modulating neural pathways (suppress pain signal transmission)
Ie - inhibiting the reuptake of these monoamines = more availability at synapses = descending inhibitory pain pathways are reinforced
List 2 classes of TCA’s and 1-2 examples of each
- Tertiary amine drugs:
- amitriptyline
- imipramine - Secondary amine drugs:
- desipramine
- nortriptyline
List 4 scenarios which warrant caution with TCA use
- significant heart disease
- risk factors for QTC prolongation
- Cognitive impairment
- Fall risk
- Acute close angled glaucoma
A patient has tolerated amitriptyline well but has only had partial relief despite the dose being at the maximum indicated for analgesic use.
* What should be done with the dose of this medication?
*What should be checked at relatively high doses?
* What type of TCA is amitriptyline and how does this differ from nortriptyline?
Given evidence of dose-dependent analgesic effects, it is reasonable to continue upward dose titration BEYOND usual analgesic doses in patients who fail to achieve benefit and have no limiting SEs. Note: there is no justification for increasing doses beyond the levels associated with antidepressant effects.
ECG to evaluate cardiac rhythm and QTC interval
Amitriptyline is a tertiary amine - more SEs, but better evidence for efficacy
Nortriptyline is a secondary amine - less SEs, but less evidence for efficacy
List two clinical contraindications for TCA
- narrow angle glaucoma
- recent MI
Note: caution in elderly, medically ill, CV disorders (QTC prolongation), seizure hx
List 4 side effects of TCAs (besides anticholinergic effects)
List 7 clinical findings of an anticholinergic toxidrome
Sedation, seizure, orthostatic hypotension, weight gain
Mad as hatter, blind as bat, red as beet, hot as hare, dry as bone, heart runs alone, bladder/bowel lose their tone
- How do SNRI’s compare with TCA’s re: side effects.
- i) What is the evidence for SNRI’s re: analgesic effect.
ii) Which SNRI is preferred? Name 3 SNRIs
iii) What is the approach to dose titration? - Give 2 examples of oncology treatment related pain syndromes and 1 SNRI shown to be helpful in each case
- How do SSRI’s compare with SNRI’s re: efficacy in pain
- SNRI’s have more favourable side effect profile than TCA’s
- There is high quality evidence for some SNRI’s - mainly duloxetine, venlafaxine, and desvenlafaxine.
Duloxetine preferred given number of positive trials.
Low starting doses overlap effective dose, so titration may or may not be needed.
Can increase if no s/e but stop at upper end of antidepress. range - i) CIPN - duloxetine 30-60 mg daily (cymbalata)
ii) Oxaliplatin induced PN - venlafaxine (Effexor)
iii) Post mastectomy pain - venlafaxine - Limited evidence for a few of the SSRI’s (paroxetine, citalopram, escitalopram) therefore SNRI’s chosen when primary indication of pain
List 4 side effects of SNRIs
Nausea, headache, somnolence, tremor, nervousness, hypertension, dry mouth, diaphoresis, constipation, sexual dysfunction.
Duloxetine: dizziness, fatigue
FS: NASH (nausea, anxiety, sexy dysfunction, headache)
List two clinical contraindications for buproprion (NDRI)
- seizure disorder (eg those with anorexia/bulimia)
- use of MAOI within 14 days (can cause hypertension and bupropion toxicity)
List four side effects of buproprion
Agitation, tremor, insomnia, nausea, decreased appetite, weight loss, headache, dry mouth, somnolence, hypertension, tachycardia
FS: NASH (nausea, anxiety, sexual dysfunction - although less than SSRI/SNRI, headache)
- List 2 examples of alpha adrenergic agonists + available routes + indication
- Describe their mechanism for analgesia
- Overall limited evidence for their use but:
Clonidine - orally, transdermally, epidural. Epidural clonidine effective for various cancer pain*
Tizanidine - oral antispasticity agent. s/e somnolence so can try 2-4 mg hs and uptitrate for pain complicated by insomnia
Dexmedetomidine - injectable sedative/hypnotic used in ICU. Evidence for pain/delirium in advanced illness*
- Activate monoamine-dependent endogenous pain modulating pathways in the brain and spinal cord (decrease pain transmission)
List three side effects of clonidine (alpha-2 adrenergic agonist)
somnolence, hypotension (usually orthostatic), and dry mouth.
tizandine - less often hypotensive due to less alpha 1 adrenergic activity
FS: think of dexmedetomidine and icu patients
What are three first line agents for neuropathic pain?
selected antidepressants (SNRIs and TCAs)
gabapentinoid anticonvulsents
in context of advanced illness corticosteroid may also be firstline
- What are cannabinoids?
- Which receptors do they act on?
- List 2 examples of synthetic cannabinoids and for each:
- Name brand name
- Name composition (THC vs CBD) - Name 2 painful clinical condition in which there is evidence their use
- Cannabinoids are related to chemical constituents of cannabis
- Bind to cannabinoid receptors
i) Nabiximols (THC 50% + cannabidiol 50%)
- Sativex
- oromucosal formulation - to spray
-complex dose-response curve (efficacy for pain at low-med doses, but not high doses)
ii) Nabilone (THC)
- Cessamet
- oral synthetic
- spasticity in MS, opioid-refractory cancer pain
** Studies of cannabis itself also support analgesic efficacy
List 4 side effects of pharmaceutical cannabinoids
- Dizziness
- Somnolence
- Dry mouth
- Psychotomimetic effects related to THC
- How do topical analgesics work? When should they be considered?
2.What is 1 benefit of this approach?
- What is the evidence for topical analgesics? (List 1 example for strong, moderate, low quality evidence)
- Deliver low doses of analgesic compounds directly to painful site. Consider for local or regional pains.
- Limited systemic absorption so low risk of side effects.
- Strong evidence:***
Topical NSAIDS (diclofenac, ketoprofen) in acute and chronic MSK pain
Topical baclofen, amitryptiline, ketamine for CIPN (1 study)
Moderate quality evidence for limited effect:***
High [conc] Capsaicin in herpetic neuralgia
Very limited evidence for other NSAIDs, low [conc] capsaicin, lidocaine, clonidine, herbal.
Little supporting evidence for topical amitriptyline, doxepin, baclofen, ketamine, gabapentin, and menthol. No data on dose, additive effects, formulation.
(So overall, other than NSAIDS, evidence is lacking and use is derived from ++ clinical experience)***
- Name 4 non-cancer syndromes that may respond to botulinum toxin.
- Botox has favourable response in cancer patients with chronic post treatment pain syndromes. List 2 limitations to its use
- peripheral neuropathic pain
plantar fasciitis
piriformis syndrome
post-surgical pain
joint pain
low back pain
osteoarthropathy
(No evidence in carptal tunnel, myofascial pain) - Cost and availabilty
FS:
migraine
TMJ pain
Esophageal spasm
Bladder spasm
- What is the evidence for neuroleptics in pain management?
- List atleast 4 adverse effects of these drugs
- Many randomized trials have found limited evidence of analgesic efficacy. Given risk of side effects, their primary use as analgesic is NOT supported.
Potential for analgesia could influence timing/dose of neuroleptic for other indication
e.g. Case series suggest olanzapine benefit in opioid-refractory cancer pain
- EPS*
somnolence*
weight gain*
diabetes*
hypotension
arrhythmia
sexual dysfunction
FS: think olanzapine
- Mechanism of action of NMDA antagonists as analgesics?
- What is the evidence for Ketamine use in non-cancer and cancer pain.
- List 2 other NMDA antagonists (not methadone) studied with mixed results in neuropathic pain (but rarely considered for refractory pain)
- Activation of the NMDA receptor is associated with peripheral and central sensitization of pain, resulting in neuronal excitation and abnormal pain manifestations (spontaneous pain, allodynia, hyperalgesia) -> blocking NMDAR (by not allowing glutamate binding) therefore decrease pain
- Ketamine - systematic reviews in CRPS support ketamine as multipurose analgesic. Insufficient evidence in cancer pain.
- Memantine*
Amantadine
Dextromethorphan*
- List 4 different approaches to starting and titrating Ketamine for pain control
- Intranasal ketamine (but used in acute pain, need more experience to suggest in chronic pain)* (FS: 10mg intranasal Q2H PRN)
- Burst therapy for severe pain:*
- brief infusion, i.e. 100 mg/day, inc by 100mg/day for 3-5 days.
- risk AE with rapid dose escalation - Continuous infusion protocols i.e. loading bolus 0.1-0.5 mg/kg, then 0.05-0.2 mg/kg/h. Can increase rate q few hours if still pain and no major s/e*
- Alternative approach for infusion irrespective of weight:
50-100 mg/day, increase by 25-50% every day - Oral ketamine 10-25 mg PO 3-4 times per day then titrate up until benefits or side effects*
(Retrospective study: mean effective oral dose 2mg/kg)
- List 3 cognitive side effects of ketamine
- List 2 ways to reduce the risk of side effects.
- dysphoria
dissociation
hallucinations - Side effects are generally lower with subanesthetic doses, but can consider:
- co-admin of benzo or neuroleptic
- reduce opioid pre-emptively by 25-50% when initiating ketamine
FS: k hole, psychomimetic symptoms
- How do gabapentinoids work on pain?
- What is the evidence for their analgesic efficacy (cancer versus non cancer pain)
- Bind to alpha-2 delta site of voltage gated calcium channel -> reduce calcium influx -> decrease likelihood of depolarization –> decrease release of excitatory neurotransmitters (substance P etc) = decreased pain transmission
- Considered multipurpose analgesics due to efficacy in pre-emptive analgesia, acute pain, neuropathic pain.
Evidence in chronically ill population for opioid refractory pain is inconclusive.
What are 3 limitations of evidence-based guidelines for neuropathic pain published by several professional societies (i.e. NeuPSIG, NIHCE, CPS)*
- Vary substantively in interpretation of the best available evidence
- Applicability to populations with serious chronic illness unknown
- None discuss use of glucocorticoids, important adjuvant in cancer related neuropathic pain
What does the Canadian Pain Society list as 1st, 2nd, 3rd, and 4th line agents for neuropathic pain? Give 1 example of each
Table 7.9.2:
FIRST line:
gabapentin/pregabalin
SNRI
TCAs
SECOND:
tramadol
strong opioids
THIRD:
cannabinoids
FOURTH:
other opioids (methadone/tapentadol)
Botox
lacosamide
lamotrigine
lidocaine cream
lidocaine patch
List four side effects of gabapentinoids
- Sedation*
- Delirium*
- Nausea
- Dry mouth*
- Peripheral oedema*
- Weight gain
- Headache
SS:
NB - are not metabolized in liver
Have no known drug-drug interactions per oxford?
- How might patients respond to gabapentin vs. pregabalin?
- Is one more effective or preferred over the other?
- In the medically frail, what are appropriate starting doses for each medication?
- What is the range of an effective dose for each?
- Patients may be responders to one, both, or none.
- 1 trial in cancer-related neuropathic pain = pregabalin superior to gabapentin but has not been replicated.
Pharmacokinetics of pregabalin supports easier/rapid titration
- Pregabalin: 25-50 mg/day
Gabapentin: 100-200 mg/day
Titration every few days until benefit or side effects occur
- Pregabalin: 150-600 mg/day
Gabapentin: 900-3600 mg/day
(FS: 4x range)
Is there evidence for other anticonvulsants in patients with opioid-refractory neuropathic pain that has not responded to the analgesic antidepressants and gabapentinoids?
- Per Cochrane reviews, no high quality evidence that other anticonvulsants are analgesic in neuropathic pain
BUT per Oxford text, other reviews/clinical experience says to consider trial in opiod refractory neuropathic pain (??):
- carbamazepine (in trigeminal neuralgia but ++ heme toxcity)
- phenytoin, valproate (limited evidence, ++side effects)
- oxcarbazepine in peripheral neuro pain
- lacosamide, topiramate in painful diabetic neuropathy
- lamotrigine in some neuro pain but no in CIPN
- no evidence for levetiracetem
-
- GABA agonist - mechanism of action?
- What evidence is there for analgesic effect of GABA agonists?
- List 2 meds and for each 1 condition when it might be useful
- GABA agonists: increase chloride ion influx -> neuron hyperpolarization -> inhibition of neuronal transmission
- Limited evidence for their effect in pain
- i) Clonazepam - if pain accompanied by severe anxiety
ii) Baclofen - management of spasticity
*** taper to avoid withdrawal seizures
A patient is receiving a lidocaine infusion. List 3 side effects that may occur with each of the following:
- Low (safe) blood level of lidocaine
- Medium blood level
- High blood level
Low:
1. Numbness, tingling (perioral, fingers, toes)
2. Metallic taste in mouth
3. Ringing in ears
4. Lightheaded or dizzy
Med:
1. Facial twitching
2. Nausea and vomiting
3. Decreased hearing
4. Severe dizziness
High:
1. Convulsion/seizure
2. Cardiac arrest*
3. Respiraory depression*
4. Loss of consciousness
Fs:
LoC
Seizure -> twitching -> tingling
Resp depression -> nv-> metallic taste
Cardiac arrest -> decrease hearing -> ringing
List three contraindications to the use of ketamine as an adjuvant analgesic
- Increased ICP*
- Uncontrolled seizure
- Hypertension*
- Heart failure, angina or recent MI
- Psychotic disorders*
List four side effects associated with the use of ketamine
- Sedation *
- Sympathomimetic: Hypertension, tachycardia*
- Psychomimetic (K hole): hallucinations, dysphoria, vivid dreams*
- symptoms of increase ICP - nausea *
- Tonic–clonic movements or tremor
- Nystagmus or diplopia
- Airway resistance
- myocardial depression
FS: think of CIs
List two agents with evidence for the management of trigeminal neuralgia
baclofen and carbamazepine
What receptor does capsaicin act on?
What is the effect?
How must capsaicin patches be used?
FS: only last question is in 6th version of book
Topical capsaicin:
1. Bind to the transient-receptor-potential-vanilloid type 1 (TRPV1) receptor
2. Inhibit release of substance P and other compounds
3. Less signal to afferent C-fibers
- Low dose patch (0.075%) - apply for a week, for regional neuropathic pain and joint pain*
- High-dose capsaicin patch (8%) - apply for 30 min, for post-herpetic neuralgia* and HIV-associated painful peripheral neuropathy (duration of effect can last several months)
List 3 ways to reduce SRE’s (skeletal-related events) in patients with multiple metastases
- Conventional anti-cancer therapies
- Bone-targeting medical therapy
- Calcium and vit D supplements
List 4 treatments for bone pain
- Corticosteroid
- Octeoclast inhibitors
- Radioisotope
- If refractory pain, concurrent trial of multipurpose analgesic reasonable, usually antidepressant, given neuropathic process in bone pain
3 examples of osteoclast inhibitors?
- Bisphosphonate - Pamidronate, ZA
- Calcitonin
- RANKL Inhibitor - Denosumab
The use of bisphosphonates as adjuvant analgesics reduces skeletal-related events - what are 4 examples of this?
- Bone pain
- Pathological fractures
- spinal cord compression
- hypercalcaemia
- necessity for radiation to adress impending fracture
- Need for bone surgery
- How do osteoclast inhibitors work for metastatic bone pain?
- What is the evidence for their analgesic efficacy?
- Mechanism is not certain : Inhibit osteoclast -> reduce bone resorption -> reduce bone pain
- Early studies - ZA decreases bone pain from breast, prostate, lung cancer, and multiple myeloma
2016 systematic review of bisphosphonates - reduce pain, rapid onset, relief for 1-3 months but positive effect on QOL not decomstrated
List 2 common, 2 less common, and 2 rare side effects of bisphosphonate therapy
Common:
1. Transitory flu-like syndrome
2. Upper GI symptoms with oral therapy*
3. AKI (contraindicated in severe renal insufficiency) *
Less common:
1. Ocular inflammation
2. Severe MSK pain*
3. Hypocalcemia*
Rare:
With treatment for months/years: Osteonecrosis of the jaw
Atypical femur fracture
In cancer patients, the risk of jaw pathology from bisphosphonate use is directly associated with what 3 factors:
- cumulative dose/duration of bisphosphonate
- comorbidities: dental pathology, diabetes
- concurrent drugs: longterm glucocorticoid therapy
- How does denosumab work as an osteoclast inhibitor?
- It is said to be effective for bone pain. How does it compare to bisphosphonates re:
i) efficacy for SRE’s
ii) adverse effects
- It is a human monocolonal antibody that binds to RANKL and prevents activation of osteoclasts -> reduce bone resorption.
i) Studies favour denosumab over bisphosphonate
ii) Denosumab more likely to cause hypocalcemia and less likely to case renal toxicity
- What are 2 relative contraindications for radioisotope therapy for bone pain?
- What is the efficacy of radioisotope therapy on pain relief?
- What is the evidence for radioisotopes vs osteoclast inhibitors in bone pain?
1.
i) existing bone marrow suppression (as risk of leukopenia, thrombocytopenia)
ii) Renal insufficiency
- meaningful pain relief to 75% patients, and complete to 10-25%
- Insufficient data to compare with osteoclast inhibitors
**Cost, complexity of treatment & risk of toxicity as above likely limits use of radioisotopes
List three classes of drugs that are helpful as adjuvant analgesics in the setting of bowel obstruction. Give an example of a drug from each class
Anticholinergic drugs - theoretically relieve the symptoms of bowel obstruction by reducing propulsive and non-propulsive gut motility and decreasing intraluminal secretions - hyoscine butylbromide (buscopan) > hyoscine hydrobromide (scopolamine)
Somatostatin analogues - inhibits the secretion of gastric, pancreatic, and intestinal secretions and reduces gastrointestinal motility. Octreotide
Corticosteroids - dexamethasone
List two muscle relaxants that can be used for MSK pain or MS spasticity
FS: not in oxford 6th edition
- Anticholinergic (cyclobenzaprine)
- Gaba agonist (baclofen, benzo)
- Alpha-2 adrenergic agonist (clonidine, tizanidine)
Note: there is actually no evidence that these drugs relax skeletal muscle in the clinical setting. They should not be administered in the mistaken belief that they relieve muscle spasm.
List five medications that can be used topically
ketamine amitryptiline lidocaine opioids NSAIDS baclofen capsaicin
Why should SNRIs be tapered slowly and not d/c’d abruptly?
rapid discontinuation may lead to seratonin withdrawal (FINISH) and worsening agitation or anxiety
FINISH =
- Flu like symptoms
- Insomnia
- Nausea
- Imbalance
- Sensory disturbance
- Hyperarousal
Significant adverse effect of carbamazepine:
leukopenia
