Table 3.

Pharmacologic components of multimodal analgesia for perioperative pain relief for lower limb amputation (LLA).

Component	Representative drug/dose	Comments	References
Regional anesthesia		Various regional anesthesia techniques: epidural, spinal, and peripheral nerve block catheters.
Example: stump catheter	Bupivacaine 0.125–0.25%	Continuous infusion of 4–14 mL/hr (may add bolus 2–5 mL with lockout of 20–60 minutes). Continue for 4–5 days postoperatively.	[26–28]
	Ropivacaine 0.1–0.5%	No benefit in prevention of PLP (of possible benefit if extended over a longer period of time perioperatively).	[19, 29]
Opioid analgesics	Variety of agents	May be of use for short term or breakthrough pain control postoperatively. Use lowest doses that provide adequate analgesia with tolerable side effects. Wean as soon as possible and try to avoid long-term use. Intravenous or oral morphine may reduce PLP but has significant side effects.	[15, 20, 21]
Systemic nonopioid analgesics	Acetaminophen: up to 4000 mg/day for 3–5 days duration	Reduction of dose in debilitated patients. Good safety profile but use cautiously in patients with hepatic impairment.	[13, 24]
	NSAIDS: variety of agents	For breakthrough pain if renal function adequate and no contraindications. Routine or long-term use in the elderly is not recommended due to GI and renal toxicity.	[9, 24, 25]
Gabapentinoids	Gabapentin: 100 mg BID to TID, up to 1200 mg TID maintenance	Start with low dose and gradually titrate to an increased dose every few days, up to 2400–3600 mg/day total dose. Use lower dose if poor renal function. May take several weeks to see peak effect. Dose-limiting side effects of somnolence, dizziness, headache, and nausea. Efficacy for PLP inconclusive, whether started early or late.	[10, 15, 20–22, 24, 30]
	Pregabalin: 50 mg once daily, up to 150 mg BID	Start with single daily low dose and gradually increase to twice daily only after one week, up to 150 mg BID. Consider monitoring renal function. Dose-limiting side effects of drowsiness, dizziness, ataxia, and blurred vision. Efficacy for PLP unknown.	[30]
NMDA antagonists	Ketamine low-dose IV infusion: 0.1–0.2 mg/kg/hr for 24–72 hours (for acute pain) or 0.4–0.5 mg/kg infusion over 45–60 minutes (therapy for chronic PLP)	Caution with hepatic impairment. Contraindicated with elevated intracranial or intraocular pressure, globe injuries, high-risk coronary or vascular disease, history of psychosis, sympathomimetic syndrome, recent liver transplantation, and porphyria. Only limited studies when infusions used for acute pain treatment for LLA. Some reports of short therapeutic infusions for established chronic PLP.	[10, 11, 20, 21, 22, 31]
	Oral dextromethorphan 60–90 mg BID for 10 days (therapy for chronic PLP)	Limited small studies in (cancer) amputees. Dose-related side effects of tachycardia, respiratory depression, nausea, vomiting, hallucinations, and acute changes in memory and cognition. Thus, avoid doses above 2 mg/kg.	[10, 20, 21, 22, 32]
		Ketamine and dextromethorphan (but not memantidine) have shown some benefit in treatment of PLP but are limited by side effects.	[10, 11, 15, 20–22]
Antidepressants	Amitriptyline 25 mg TID (or 50–100 mg once daily at bedtime) titrated to maximum 150 mg/day	For geriatrics, start amitriptyline at 10 mg once daily at bedtime, increase weekly by 10 mg/day. Side effects are dry mouth, drowsiness, sedation, orthostatic hypotension, constipation, urinary retention, weight gain, and arrhythmia. Contraindicated in glaucoma, prostatism, and significant cardiovascular disease.	[10, 11, 21, 22, 33, 34]
	Nortriptyline 25 mg TID titrated to maximum 150 mg/day	For geriatrics, start nortriptyline at 10 mg once daily, increase weekly by 10 mg/day. Similar precautions as per amitriptyline. If adequate pain relief is obtained with amitriptyline but unable to tolerate side effects, consider a trial of nortriptyline.	[13, 30, 34]
	Mirtazapine 15 mg once daily at bedtime titrated to maximum 45 mg/day	For geriatrics, start mirtazapine at 7.5 mg once daily at bedtime.	[35]
		One study showed success in abolishing PLP with amitriptyline and tramadol in young, posttraumatic amputees. One case report of four patients who exhibited a marked (>50%) reduction in PLP with the use of mirtazapine.	[33, 35]