Adjuvant Analgesics Flashcards
Adjuvant analgesics: Deifnition
- Term may be outmoded - historically was any drug that had a primary indication other than pain, but now many drugs have multiple indications or are primary analgesics
Could now be considered both as ‘add-on’ therapy to an opioid regimen and distinct, primary therapy in painful disorders when likely to demonstrate a good response
Limitations of adjuvant analgesics
As a group, less reliable than opioids:
- Small proportion of treated patients with adequate response
- Higher likelihood of troublesome side effects (especially related to polypharmacy)
- Slower onset of analgesic effect
- Significant interindividual and intraindividual variability in response to adjuvants
Best to optimize opioid therapy first (where there is inadequate pain management despite dose escalation to limiting side effects), then add an adjuvant
Classes of adjuvant analgesics: Multipurpose adjuvants
- Anti depressants (TCAs, SNRIs, SSRIs, Bupropion)
- Corticosteroids (Dex)
- Alpha-2-adrenergic agonists (clonidine, Tizanidine)
Classes of adjuvant analgesics: Adjuvants for neuropathic pain
First line:
- Gabapentinoid anticonvulsants (likely preferred)
- Antidepressants (TCA - amitriptyline, SNRI - duloxetine)
- Corticosteroids
- Topical anesthetics if localised
Other drugs:
- Oral and parenteral sodium channel blockers
- NMDA receptor blockers
- Cannabinoids
- Baclofen
Classes of adjuvant analgesics: Topical analgesics
Capsaicin
Local anesthetics
NSAIDs
TCAs
Classes of adjuvant analgesics: Adjuvants for bone pain
Calcitonin and bisphosphonates
Radiopharmaceuticals
Corticosteroids
Classes of adjuvant analgesics: Bowel obstruction
Anticholinergics
Octretoide
Corticosteroids
Antidepressants as adjuvants (Indications, Evidence, Dosing and Titration, Drug Selection)
Indications
- Difficulty with favourable balance between analgesia and side effects with an opioid
- Comorbid depression or anxiety
Evidence
- Very little, evidence mainly from observational studies
Dosing and Titration
- Analgesia appears to be dose-dependent with TCAs
- Onset of effect typically within a week of an effective dosing level, with maximal effect evolving over days and weeks after
Drug selection
- No guidelines for drug selection
- Typically trial and error
- Substantial variability in analgesic response to different antidepressants - consider trial of an alternative if one does not work
- If there is partial response to one antidepressant, may consider combining drugs in different classes (e.g. TCA and SNRI)
TCAs as adjuvants (Evidence, side effects)
Evidence
- Analgesic efficacy in a variety of chronic pain syndromes, especially neuropathic pain
- Evidence is strongest for tertiary amine compounds (amitriptyline), but secondary amines (nortriptyline) preferred because of lower toxicity/side effects
Side effects
- Minimise by starting with a low dose and titrating slowly
- Sedation, confusion
- Orthostatic hypotension
- Heart block
- Weight gain
- Tachycardia
- Seizure
- Arrhythmia
- Anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation, delirium etc.)
TCAs as adjuvants: Examples and starting doses
Amitriptyline 10-25mg HS
- Usual effective dose 50-150mg HS
- More evidence, but more side effects
Nortriptyline 10-25mg HS
- Usual effective dose 50-150mg HS
- Less side effects, but less evidence
Start at HS due to sedating side effects
NNT 2.1 - 2.8
TCAs as adjuvants: precautions/contraindications
Precautions
- Elderly and medically ill (anticholinergic effects)
- CV disorders (heart block, arrhythmia, tachycardia are potential side effects, especially at higher doses)
- Urinary hesitancy (anticholinergic effects)
- Seizure disorder (lower seizure threshold)
Contraindications
- Narrow angle glaucoma
- Recent MI
TCAs as adjuvants: Drug interactions
Cardiac arrhythmia
- QTc prolonging drugs
- Beta blockers
- Class IC antiarrhytmics (propafenone, flecainide)
Anticholinergic effects
- May enhance anticholinergic SE of other drugs
Serotonin syndrome
- Caution with MAOIs, Ondansetron, serotonergic opioids (tramadol, methadone, fentanyl)
Bleeding risk
- Caution with NSAIDs (antiplatelet effects)
CNS depression
- Caution with any sedating drugs
CYP2D6 interactions (TCAs are substrate) - SSRIs metabolised by CYP 2D6 (amitriptyline, venlafaxine, fluoxetine, paroxetine, citalopram, duloxetine and mirtazapine)
SNRIs as adjuvants: Agents, starting dose, usual effective dose
Duloxetine 30mg qDaily, up to 60mg qDaily
Venlafaxine XR 37.5mg qDaily, up to 150-300mg PO qDaily
NNT 5.0
Duloxetine effective in week 1, most effective dose with fewest side effects is 60mg qDaily
SNRIs as adjuvants: Evidence, side effects
Evidence:
- Only antidepressants other than TCAs with evidence of analgesic efficacy
- Evidence for postoperative pain (mastectomy) and neuropathic pain
Side effects:
- Nausea (most common)
- Headache
- Somnolence
- Tremor
- Nervousness
- Hypertension
- Dry mouth
- Diaphoresis
- Sexual dysfunction
- Constipation
- Hypertension (monitor BP, especially with venlafaxine)
Duloxetine - dizziness and fatigue
SNRIs as adjuvants: precautions/contraindications
Hypertension
- Caution with Venlafaxine, monitor BP
Seizure disorders
- May lower seizure threshold
Renal impairment
- Dose reduce by 25% if mild-moderate, or by 50% in dialysis patients
Hepatic dysfunction
- Avoid duloxetine
Discontinuation syndrome
- Taper gradually when discontinued - otherwise may lead to agitation, anxiety, insomnia
SNRIs as adjuvants: Potential drug interactions
Serotonin syndrome
- Increased risk with venlafaxine when combined with MAOIs, TCAs, bupropion, SSRIs, some HIV/AIDs meds
Bupropion as adjuvant: Evidence and side effects
Evidence
- Evidence for pain relief in neuropathic pain in one RCT
- Low risk of side effects that may be limiting for other patients, and may help with fatigue
Side effects - Agitation - Tremor - Insomnia - Nausea - Weight loss - Decreased appetite - Headache - Dry mouth - Somnolence - Hypertension Tachycardia
Bupropion as adjuvant: Starting dose and target dose
Starting dose - 75mg PO qDaily
Usual effective dose - 75 - 150mg PO BID or TID
Bupropion as adjuvant: Precautions/contraindications
Contraindications
- Seizure disorder (lowers seizure threshold)
- Anorexia/bulimia (effects on weight and seizure threshold)
- Use of MAOI within 14 days (Serotonin syndrome)
Bupropion as adjuvant: Drug interactions
- Toxicity increased by levodopa and amantadine
- Watch for other agents that lower the seizure threshold
Steroids as adjuvants - evidence
Numerous studies:
- Improve appetite, nausea, malaise, quality of life
- Toxicity means that steroids can be used as an analgesic in only those with shorter life expectancies
Helpful in:
- Neuropathic pain (infiltration or compression)
- Bone pain
- Headache from increased ICP
- Arthalgia
- Obstruction of a hollow viscus (bowel or ureter)
- Liver capsular pain
Steroids as adjuvants: Choice of agent
- Dex often preferred due to relatively low mineralocorticoid effects
Steroids as adjuvants: Starting dose of dex
High dose start (e.g. initial dose of 20-100mg, with 32-96mg q Daily)
- Very severe pain, such as rapidly worsening malignant plexopathy
- Cord compression or cauda equina
- SVC syndrome
Low dose regime (e.g. 2-4mg/day)
- Suboptimal pain control with opioids
- Weakness and low energy
In general, as per CBM, should only rarely exceed 24mg/day. Half life is long (36 hrs), but dose may be divided to prevent GI side effects
Side effects of steroids
Long term:
- Weakness,
- Aseptic necrosis
- Osteoporosis
- AI (with illness or abrupt cessation of treatment)
Short term
- Cutaneous effects
- HTN
- Hyperglycemia
- Pancreatitis
- Immune dysfunction
- Neuropsych impacts
- GI upset/bleeding
- Insomnia
Alpha-2-agonists
E.g. clonidine or tizanidine
Evidence for cancer pain, diabetic neuropathy, myofascial pain syndrome
- Limited experience in advanced illness, usually not used unless other adjuvants (e.g. anticonvulsants, antidepressants) have failed
Neuroleptics
- Eg. olanzapine
Research suggesting that atypical antipsychotics (such as olanzapine) may decrease opioid unresponsive cancer pain by potentiating effect of opioids
Little evidence to support, but could be considered if there is also delirium or nausea or other drugs unsuccessful
Anticonvulsants for neuropathic pain: Evidence
- Mixed evidence for analgesic efficacy, but experience suggests otherwise and they are widely used
Approach to adjuvant analgesia for neuropathic pain:
- Gabapentinoid (unless patient is depressed, in which case go straight to antidepressants). Note that pregabalin (Lyrica) is more rapidly and predictably absorbed.
- Analgesic antidepressants (Duloxetine is first line, then try a TCA)
- Steroids (consider more for short term pain crisis)
- Topical lidocaine 5% (consider if localised)
- If opioids are required due to moderate/severe pain, start with an IR opioid while adjuvants are being initiated and then switch to long acting once pain regime is stablised.
If no response to gabapentin or antidepressants, go to other anticonvulsants (e.g. lacosamide), cannabinoid
Gabapentin and pregabalin: Starting dose, effective dose
Gabapentin
- 100 PO TID
- Titrate by 100-300mg every 1-3 days to an effective dose
- Effective dose: 300-1200mg PO TID, only rarely would exceed 3600mg/day
Pregabalin
- 25-75mg PO qDaily to BID
- Usual effective dose: 150-300mg PO BID
- Additional anxiolytic effects for those with CAD
- Act as calcium channel antagonists as pre-synaptic sites
Pain relief typically within 1st or 2nd week and often results in improved sleep and QOL. Unknown if patients who don’t respond to one would benefit from the other.
NNT for both drugs is 4.2-6.4
Gabapentin and Pregabalin: Precautions and contraindications
Renal dysfunction
- Dose reduce in renal dysfunction
- Avoid in severe real dysfunction
Discontinuation syndrome
- Rapid discontinuation may result in headache, nausea, insomnia, diarrhea
Gabapentin and Pregabalin: Drug interactions and side effects
- No significant interactions
Side effects
- Most significant side effect is sedation
Lacosamide: Starting dose and usual effective dose
Lacosamide 50mg PO BID
- Titrate to 200-400mg PO BID
Lacosamide: Precautions/contraindications, drug interactions, adverse effects
Renal disease
- Dose reduce for CrCl < 30
Hepatic disease
- Dose reduce
Side effects:
- Nausea
- Dizziness
- Drowsiness
- Fatigue
No sig drug interactions for palliative care
Very limited evidence, CTs are mixed
Lidocaine (sodium channel blocker) as analgesics
- Prolonged relief of pain following a brief IV infusion of lidocaine is possible, though evidence is weak
- Typically 2-4mg/kg over 20-30minutes in the case of severe neuropathic pain
- Allows for reduction of pain such that other strategies can be implemented
- Anecdotal reports of long term administration
NMDA antagonists as adjuvants: Evidence
- Interactions at the NMDA receptor are involved in CNS changes that may modulate opioid mechanisms (including sensitization and neuropathic pain)
- Includes ketamine (infusion protocols) and D-isomer of methadone
NMDA Antagonists: Ketamine - Evidence, starting dose and effective dose
- Some evidence for it as an analgesic, though not well supported by RTs
- In general, consider if there is failure of two or more courses of strong opioids plus adjuvant analgesics in cancer pain
Starting dose: Different IV or subcutaneous regimens
Note that PO dosing is more potent than parenteral, likely due to production of norketamine as metabolite (more potent analgesic than the parent compound)
Ketamine: Precautions and contraindications
Contraindicated with:
- HTN
- CHF
- Angina
- Aneurysms
- Cerebral trauma
- Recent MI
Use caution with:
- Psychotic disorders
- Thyrotoxicosis
- Tachycardia
- Seizures
Ketamine: Drug interactions
- Increased ketamine levels/effects with CYP3A4 inhibitors
Ketamine: Adverse effects:
- HTN
- Tachycardia
- Tremor
- Nystagmus
- Diplopia
- Airway resistance
- Myocardial depression
- Tonic clonic movements
- Vivid dreams/dissociative state (especially during initial infusion)
- Drowsiness
- Confusion
- Dry mouth
- Pyoderma gangrenosum (if injected subcut)
Consider use of concurrent benzo or neuroleptic to blunt or prevent these effects, particularly during the initial infusion. Recommend Midaz or Haldol
High risk of neurotoxicity given the number of neurotransmitter systems it affects
Sativex: Indications, use, side effects
- Consider for pain refractory to opioids and other adjuvants (anticonvulsants, antidepressants), best evidence for spasticity related to MS
- Start at one spray BID, then titrate - often 4-8 sprays daily
Side effects:
- Dizziness, fatigue, Nausea
Nabilone: Indications, use, side effects
- Indicated for refractory nausea and vomiting, but may be helpful for pain (especially spasticity related)
- Start at 0.5mg - 1mg QHS and titrate up to 3mg BID
Side effects:
- Dizziness, drowsiness, fatigue, dry mouth
Topical anesthetics
- Delivers low dose of analgesic compounds directly to the site responsible for pain, with lower risk of systemic toxicity
- Capsaicin preparations
- NSAIDs
- Topical TCAs
- Topical lidocaine
Capsaicin - adjuvant analgesic: Mechanism of action, indications
- Inhibits polymodal primary afferent nociceptive neurons (C fibres) by inhibiting substance P
- May be effective in neuropathies, including after cancer surgery
- Application can be painful and requires prior application of local anesthetic
- Long term effect with no systemic side effects
- Cutaneous patch of 8% capsaicin authorized in Europe
Topical NSAIDs: indications
- May be useful for MSK pains
- Some systemic absorption (so if there are strong contraindications, avoid)
Topical local anesthetics: Indications
- Used prior to procedures (e.g. needle puncture)
- Low risk of systemic toxicity, but if applied repeatedly to mucous membranes or open wounds, should monitor
- Use Topical lidocaine 5% as either gel or patch, shown to be efficacious in post-herpetic neuralgia with virtually no side effects
Topical TCAs: Evidence
- May be considered for focal neuropathic pain, though evidence is limited
Adjuvants for bony mets:
- Rads - indicated for pain poorly controlled by opioids or if there is a lesion prone to fracture on XR
- NSAIDs or steroids
- Calcitonin, starting at 100IU subcut daily - but test with 1IU subcut first for hypersensitivity
- Bisphosphonates
Adjuvants for bony mets: Calcitonin
- Mixed evidence
- Test dose with just 1 IU subcut first given risk of hypersensitivity, especially with any history of allergy to salmon or seafood
Side effects: N/V
Aduvants for bony mets: Bisphosphonates
Pamidronate SC q4 weeks
Zoledronic acid 4mg IV q4 weeks
Precautions/contraindications:
- Check and monitor renal function
- Risk of GI toxicity (N/V etc.)
Adverse effects - Renal toxicity - Flu like reaction (tx with NSAIDs and tylenol) GI toxicity (only when given PO) - Osteonecrosis of the jaw
Adjuvants for MSK pain
- Muscle relaxants (methocarbamol)
- Poor evidence, but some studies have shown superiority to acetaminophen
- Do not actually relax muscles - if spasm is suspected, consider a benzo or baclofen
Steroids over time
If taken for more than two weeks, taper slowly to avoid adrenal insufficiency (can be fatal)
Buscopan
- Useful for crampy or colicky bowel or genitourinary pain
- Anticholinergic
- Start with 10mg PO/SC TID PRN, max 60mg/day
No dose adjustment with renal/liver failure, but caution advised
Baclofen
- Muscle spasm
- Inhibits the transmission of both monosynaptic and polysynaptic reflexes at the spinal cord level, possibly by hyperpolarization of primary afferent fiber terminals, with resultant relief of muscle spasticity
Dosing:
- Start with 5-10mg PO TID PRN, in severe spasticity may go up to a total of 120mg/day
Discontinuation syndrome possible - taper slowly
Dose reduce for renal dysfunction according to CrCl
May be given intrathecally with high CSf concentrations possible without same side effects
Side effects:
- Dizziness, nausea, vomiting, drowsiness, confusion
Methotrimeprazine
- Analgesic properties that may be particularly useful if pain is complicated by agitation or delirium
- May also help nausea
Start at 5-20mg PO/SC q4-8h
Side effects:
- Sedation, anticholinergic side effects, hypotension
Ketamine: Mechanism of action
- Potent, non-competitive NMDA-receptor antagonist
- Influences essentially all neurotransmitter systems in the brain (e.g. dopaminergic, adrenergic, serotonergic)
- Appears to reverse opioid tolerance
Ketamine: How to initiate *check Care Beyond Cure for protocols and PO conversion
- Start with premedication with either haloperidol or midazolam
- Scheduled dose of ketamine
- Dose increase q1-2 days depending on effect. Some patients may only respond to higher doses, but should see at least partial analgesic effect before escalating the dose
- Opioids typically maintained at the same dose or lower
- Ultimately can likely switch to PO dosing, but note that dosing would be lower
Alternative: ‘Burst’ therapy
- Subcut infusion, titrate upwards to effect
- Administer x 5 days then stop
Evidence for cannabinoids in pain
- Very mixed
- One meta-analysis found moderate evidence that cannabis could reduce chronic non-cancer pain by 30%, but adverse event rates were high (NNT = 24, NNH = 6)
- As per UTD, no data to support smoked, vaporized, or ingested cannabis for cancer pain and its use cannot be recommended
- As per UTD, Sativex may be considered as an adjunct for cancer pain refractory to opioids, with nabilone as second line
- Oxford: Analgesic efficacy established for some drugs, (e.g. Sativex - nabiximols, nabilone)
Cannabis for pain - MOA
- Cannabinoids act on the endocannabinoid system
- Cannabinoid receptors are found throughout the CNS and PNS (CB1) and organs/tissues (CB1) as well as immune tissue (CB2 - eg lymph nodes)
- Overall effect of CB1 receptor activation is inhibition of neurotransmitter release, while CB2 inhibits cytokine/chemokine release and modulates the immune system
- Bottom line: May act as an anti inflammatory (CB2) and attenuate synaptic transmission of pain (CB1)
- THC is a CB1 and CB2 agonist, while CBD acts as a type of ‘reuptake inhibitor’ and raises endocannabinoids in CNS tissue
Cannabis for pain - Side effects
Short term:
- Somnolence and dizziness
- Dry mouth
- Nausea/Vomiting
- Fatigue
- Euphoria
- Disorientation
- Drowsiness
- Confusion
- Loss of balance
- Hallucinations
- CV effects (postural syncope, MI, arrhythmias - reported, but frequency unknown)
Cautions with cannabis for pain
- Differences in cannabinoid concentrations across strains and available products
- Inability to stipulate, know, or titrate the dose taken by the patient
- Lack of information regarding drug-drug interactions
- Concerns regarding respiratory effects/cancer risk in smoking cannabis
- Specific risks in patients who have a previous history of substance abuse or chronic marijuana use
How to approach a situation where a clinician is concerned about a patient’s motive for using medical marijuana?
- Consider a random urine drug screen for other drug use that may not have been prescribed
- Have a frank discussion about the need to distinguish between recreational substance use and medical use
- Ensure that patient agrees not to take recreational substances without informing the care team given risks of toxicity
- Request a consult with a psychiatrist with expertise in recreational substance use to support the team in prescribing analgesia appropriately
- Ensure consistent team approach (limited number of prescribers, frequent urine drug testing, acknowledgement that pain control may not be as good as it may be otherwise)
- If difficulties continue, physician should suggest a written contract to ensure the patient will agrees not to divert medications, escalate doses without discussing with the team, and to disclose any recreational drugs being taken.
MOA of action of steroids in neuropathic pain
- Most valuable for pain crisis that includes neuropathic pain
- Likely results in decreased peritumoural edema and also has direct oncolytic effect on some neoplasms (e.g. lymphoma)
- Dex is preferred (lower mineralocorticoid effects)
- Higher doses can be used for a few weeks if there is severe acute pain related to malignant plexopathy or cord compression
Dextromethorphan - MOA
- NMDA antagonist
- Studied in neuropathic pain, but with mixed evidence
Sodium channel blocker: Carbamazepine/oxcarbamazepine
- Used for trigeminal neuralgia
- Comparable efficacy but fewer side effects with oxcarbamazepine
Side effects:
- Cognitive side effects (especially in elderly patients - less pronounced with oxcarbamazepine)
- Drowsiness
- Dizziness
- Ataxia
- Diplopia
- Rarely, blood dyscrasia (CBC at baseline and as part of monitoring)
- Hyponatremia (oxcarbamazepine)
Contraindications
- AV block
- Hepatic impairment
Starting dose:
- Carbamazepine 300mg q Daily (increase by 100mg every other day, max 1500-2000mg/day
- Oxcarbamazepine 600mg qDaily, increase by 150-300 every other day, max dose 1500-3000mg/daily
Topical lidocaine
- Useful for localised pain
- RCTs show benefit in post-herpetic neuralgia and mixed peripheral focal neuropathy with allodynia
- Lidocaine patch 5%, max 3-4 patches applied for 12 hours per day
Avoid in patients taking PO class I antiarrhythmic drugs (propafenone, flecainide, mexiletine, quinine, procainamide)
Side effects:
- Skin irritation
- Minimal systemic absorption is advantageous!
