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