Multimodal analgesia may include pharmacological components such as regional anesthesia, opioid and nonopioid systemic analgesics, nonsteroidal anti-inflammatories, and a variety of adjuvant agents. Multimodal analgesia has been reported for a variety of surgical procedures but not yet for lower limb amputation in vasculopathic patients. Perioperative pain management in these patients presents a particular challenge considering the multiple sources and pathways for acute and chronic pain that are involved, such as chronic ischemic limb pain, postoperative residual limb pain, coexisting musculoskeletal pain, phantom limb sensations, and chronic phantom limb pain. These pain mechanisms are explored and a proposed protocol for multimodal analgesia is outlined taking into account the common patient comorbidities found in this patient population.
Multimodal analgesia, a concept first articulated by Kehlet and Dahl [
Multimodal analgesia: pharmacological components.
Type | Examples | |
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Principle | Regional anesthesia | Central neuraxial or peripheral nerve block |
Single-shot or continuous catheter | ||
+/− local infiltration analgesia | ||
Opioid analgesics | Oxycodone, morphine, fentanyl, hydromorphone | |
Systemic nonopioid analgesics | Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) | |
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Adjuvants | Gabapentinoids | Gabapentin, pregabalin |
N-methyl D-aspartate (NMDA) receptor antagonists | Ketamine, memantidine, dextromethorphan, magnesium | |
Alpha-2 adrenergic agents | Clonidine | |
Glucocorticoids | Dexamethasone | |
Others | Antidepressant, calcitonin, nicotine, capsaicin, cannabinoid, lidocaine |
Patients will benefit from multimodal combinations that hold favourable profiles when considering the specific requirements of both their particular surgical procedure and their medical comorbidities [
Multimodal analgesia has not been described in this patient population as it has been for other surgical procedures [
Lower limb amputations are commonly performed as a consequence of long-term damage from peripheral vascular disease and diabetes mellitus. The complexity and challenge in managing pain in patients undergoing LLA begins with our limited understanding of the exact pathophysiology and mechanisms underlying the preamputation and postamputation phenomena. These patients may experience several different types of pain (individually or concomitantly) following LLA (Table
Complexity of pain associated with lower limb amputation.
Onset & duration | Comments | References | |
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Ischemic limb pain | Preoperative to intraoperative. | Pain intensity prior to amputation is a significant predictor of developing chronic limb pain. | [ |
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Residual limb pain (stump pain) | Intraoperative to 1-2 weeks postoperative. Median pain 15.5 on a 0–100 visual analog scale in the first week postoperatively. Severe pain in 5–10% of patients. | Stump pain (sharp, localized pain) gradually lessens as the wound heals. May be prolonged if complications arise such as infection, tissue necrosis, wound dehiscence, osteomyelitis, and neuroma formation. | [ |
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Phantom limb pain | Onset 1–7 days postoperative (or longer). Incidence up to 85%. Mean pain 22 on a 0–100 visual analog scale at 6 months after amputation. Severe pain in 5–10% of patients. May persist for months to years. | Symptoms: Intermittent (or sometimes constant) aching, cramping, burning, shooting, stabbing, boring, squeezing, or throbbing pains. Multiple poorly understood etiologies. | [ |
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Phantom limb sensations | Onset 1–7 days postoperative. Incidence up to 90%. May persist for months to years. | Symptoms: Nonpainful sensations that the amputated limb still exists but may feel twisted deformed or have muscle cramps, tingling or itching. Multiple poorly understood etiologies. | [ |
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Other musculoskeletal pain | Postoperative. | Back, hip, and knee pain with gait abnormalities related to changes in mechanics due to the amputated limb/prosthetic. | [ |
The majority of patients who require LLA typically have lengthy histories of ischemic limb pain and have been established on analgesic regimes that may include high doses of opioid [
Although common, phantom limb pain (PLP), a neuropathic pain, is difficult to prevent and treat since the exact underlying mechanism for the development of this phenomenon remains unknown [
Associated musculoskeletal pains such as back, hip, and knee pain have been identified as issues in the majority of LLA patients postoperatively [
Lower limb amputations are commonly performed on individuals who are predominantly elderly and have significant comorbidities. In the vasculopathic patient, significant coronary atherosclerosis is common. In fact, LLA may be associated with a 30-day mortality as high as 17% [
An assortment of pharmacological agents has been proposed for use in LLA, which may be utilized in a multimodal analgesia regime (Table
Pharmacologic components of multimodal analgesia for perioperative pain relief for lower limb amputation (LLA).
Component | Representative drug/dose | Comments | References |
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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. | [ |
Ropivacaine 0.1–0.5% | No benefit in prevention of PLP (of possible benefit if extended over a longer period of time perioperatively). | [ | |
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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. | [ |
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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. | [ |
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. | [ | |
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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. | [ |
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. | [ | |
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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. | [ |
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. | [ | |
Ketamine and dextromethorphan (but not memantidine) have shown some benefit in treatment of PLP but are limited by side effects. | [ | ||
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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. | [ |
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. | [ | |
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. | [ | |
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. | [ |
With respect to multimodal analgesia, perhaps the most profound opioid-sparing effect may be seen with the use of regional anesthesia. Immediately following amputation, there is a continuous barrage of painful sensory input that results in inflammatory changes both peripherally and centrally. Regional anesthesia interferes with the transmission of painful stimuli along the pain pathway to the cerebral cortex [
Over the years, a variety of regional anesthesia techniques have been described in the treatment of LLA. Initial reports suggested promise with the use of epidural analgesia preoperatively to prevent or reduce PLP for amputation patients [
In contrast, a recent study did show that optimized epidural or systemic analgesia initiated 48 hours preoperatively was indeed effective in reducing PLP at 6 months [
Anticoagulation issues, however, are common in the perioperative period for the vascular amputation patient which may preclude the use of central neuraxial regional anesthesia techniques. The perineural analgesia technique obviates such concerns, while providing benefits of an extended regional blockade of painful somatic stimuli postoperatively. Unlike continuous epidural or spinal anesthesia, continuous perineural analgesia is simple to administer, circumvents risks and costs, and avoids the complications of hemodynamic alterations in this highly susceptible patient population [
Fisher and Meller introduced the use of an intraincisional nerve block catheter, positioned at the distal end of the sciatic or posterior tibial nerve, which is inserted by the surgeon at the time of lower limb amputation [
This surgically placed sciatic CPNB catheter infusing local anesthetic has been shown to reduce opioid requirements and provide improved pain relief immediately and in the early postoperative phase following LLA [
Opioids are not added into CPNB infusions but are ordered concurrently, either orally or parentally, with other nonopioid analgesics to manage patients’ pain following LLA. Complications related to this technique are rare. Patients in Fisher and Mellor’s study did not complain of PLP for approximately one year following amputation [
The optimal duration for CPNB infusions is unknown, but an average duration of treatment of 4 to 5.5 days following LLA has been described [
Opioids remain the mainstay for treatment of acute pain following any surgery. Choice of opioid and dosing should be individualized and determined by the patient’s preoperative opioid requirements, age, liver, and renal function. Long-term use is not recommended as patients may develop tolerance, chemical dependence, and the potential for opioid-induced hyperalgesia [
In contrast, there is some evidence that opioids may interrupt central cortical reorganization where PLP is thought to originate [
Nonopioid and nonsteroidal anti-inflammatory drugs (NSAIDs) are appropriate for alleviating postsurgical inflammatory pain but not for the prevention of neuropathic PLP. Acetaminophen is an effective analgesic for mild to moderate pain, results in few side effects, and has a relatively safe profile. It is recommended that acetaminophen be administered only to a maximum 4000 mg daily (for only 3–5 days duration), less for debilitated patients and used cautiously for individuals with liver impairment [
It may be reasonable to add a low-dose NSAID in the short term or for treating breakthrough pain, as long as renal function is adequate and there are no contraindications. However, routine or long-term use of NSAIDs is not recommended because of the increased risk for gastrointestinal and renal toxicity in this patient population [
A variety of drugs that have shown promise in the treatment of neuropathic pain have also been investigated in the treatment of acute and chronic pain after LLA. These include gabapentinoids, NMDA receptor antagonists, antidepressants, lidocaine, calcitonin, clonidine, and Botulinum neurotoxin. Unfortunately, some of these agents have not been tested in controlled studies [
If an adjuvant was utilized preoperatively, it should be resumed in the postoperative multimodal analgesia regimen. If postoperative pain control becomes an issue, the gradual initiation of an adjuvant may be trialled [
Gabapentin has opioid-sparing effects that may be beneficial in limiting the development of opioid tolerance, if opioids are also being prescribed. However, its efficacy in treatment of PLP is inconclusive, with dose-limiting side effects of somnolence, dizziness, headache, and nausea [
The NMDA receptor antagonists ketamine and dextromethorphan have provided some benefit in reducing PLP in the short term [
With regard to antidepressants, amitryptyline was determined to have inconsistent benefits in the treatment of PLP [
Only variable results were observed in the treatment of PLP with calcitonin [
A “best practice” multimodal protocol for managing pain following LLA was created for vascular patients at our acute care hospital (Table
Perioperative multimodal acute pain management protocol for lower limb amputation (LLA).
Phase | Focus | Multimodal pain management | Comments | Precautions/references |
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Preoperative | Assess and treat acute or chronic pain before surgery. Optimize an analgesic regime based on the patient’s condition. |
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Consult the acute pain service (APS) if the patient has: |
Aggressive and early treatment of pain is needed to mitigate the severity of chronic limb pain [ |
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Intraoperative | Perineural (CPNB) “stump” catheter surgically placed: |
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For CPNB infusions: |
APS is contacted for all issues related to the CPNB catheter (i.e., disconnection, choice to continue or remove the CPNB catheter) [ |
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Postoperative day 0-1 | Control residual limb pain (RLP). Maintain the preexisting analgesic regime. Prevent opioid withdrawal. |
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APS follows patients with CPNB infusions and orders all analgesics, antipruritics, antiemetics, and sedating medications. |
Notify APS if the patient complains of persistent pain (>5/10) not relieved with an increase in CPNB infusion rate or other analgesics ordered. CPNB catheter may require a repeat bolus of local anesthetic (as intraoperatively) [ |
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Postoperative day 2–3 | Assess and aggressively treat residual limb pain (RLP) and phantom limb pain (PLP). |
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Adjust CPNB infusion rate and opioid doses along with adjuvant agents to provide adequate pain relief. |
Only use parenteral opioids (IVPB or PCA) in the early postoperative phase to manage pain. Switch to oral opioid as soon as possible [ |
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Postoperative day 3-4 | Pain management coordinated with increased activity | Maintain CPNB infusion and multimodal analgesia. | Consider consulting the chronic pain service for optimizing a long-term pain management plan. | Initiate early plans for the eventual analgesic regime, especially for complex pain patients [ |
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Postoperative day 5 | Discontinue CPNB catheter | CPNB catheter removed with initial dressing change to the residual limb (unless ordered for a longer duration by the anesthesiologist or if requested by the vascular surgery team) | Maximum period of time for CPNB catheter to remain in place: 7 days [ |
Gradually wean patient off opioid and nonopioid analgesics. Adjust adjuvant doses with the overall goal of reduction and/or eventual discontinuation |
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Postoperative day 6 and following | Management of persistent pain and/or phantom limb pain (PLP), if present | Continue multimodal analgesia agents (not including the CPNB catheter) at lowest possible doses. | Treat persistent pain like neuropathic pain. [ |
Currently there are no consensus guidelines for the optimal management of chronic PLP [ |
IVPB, intravenous piggyback; PCA, patient-controlled analgesia; APS, acute pain service; CPNB, continuous peripheral nerve block; RLP, residual limb pain; NSAID, nonsteroidal anti-inflammatory drug; GI, gastrointestinal; PLP, phantom limb pain; OSA, obstructive sleep apnea.
This protocol was developed to promote a consistent way to relieve pain in the preoperative and early postoperative phases for amputation patients, minimize opioid use and its side effects, facilitate recovery, enable earlier physiotherapy, and enhance functional outcomes. In fact, a recent large study with the use of such stump catheters has indeed confirmed its benefits and safety [
Perioperative pain management of patients undergoing LLA is indeed complex and challenging. The mechanisms of pathophysiology that underlie the postamputation phenomena of pain remain incompletely understood. Despite these issues, it is hoped that implementation of a strategy utilizing a multimodal analgesia protocol will address and enable pain control management at these multiple complex levels and pathways. Pain following LLA may interfere with an individual’s functioning, psychological well-being, and may even result in the development of chronic pain. Thus, it is important for all health care practitioners caring for patients undergoing LLA to be aware of the various analgesic options and interventions available in order to implement an aggressive pain management plan that best promotes recovery and rehabilitation. The multimodal analgesic protocol proposed here represents a compilation of commonly used agents that have been shown to be effective for LLA. Further inquiry is required to develop insight into additional approaches [
The authors confirm that there are no conflicts of interest.