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ASRA Pain Medicine Update

Approach to Pain in an Amputee

Jul 5, 2024, 10:37 AM by Rosalynn R.Z. Conic, MD, PhD, Eric Jones, MD, August Runyon, DO, and Mike Glicksman, MD

 

A 53-year-old man with a past medical history of depression, peripheral vascular disease, and poorly controlled type 2 diabetes mellitus presents to the vascular surgery clinic with a right foot pressure ulcer at the bottom of the first metatarsal, which started draining purulent fluid 4 days prior. He also reports neuropathic pain in bilateral legs, for which he is currently using gabapentin 900mg three times per day with mild improvement.

He has a BMI of 32kg/m2, and unremarkable vitals. On physical exam, he has sparse leg hair, cool feet, diminished to no sensation to monofilament testing up to the tibial tubercle, and reduced vibration sensation. His pressure ulcer is approximately 1 inch in diameter, and approximately 0.5 inches in depth, with surrounding erythema, over the plantar metatarsal head. Laboratory analysis was significant for HbA1c of 11%, WBC 12,000/ml, ESR 60mm/hr, and hs-CRP 10mg/dl. X-ray of the foot was significant for air in the subcutaneous tissue, and osteomyelitis was confirmed by MRI. He was started on antibiotics; however, he was non-compliant with dressing changes and ultimately required a below-the-knee amputation (BKA). His hospital course was complicated by persistent perception of sharp, burning, throbbing, pins/needles pain at the amputated limb.


Questions

1. Given this patient’s presentation, what is his most likely problem? What are other causes of pain in an amputee and how would you differentiate?

This patient is most likely presenting with phantom limb pain (PLP). Phantom limb pain is a common complication in amputees with 50-85% of patients reporting this pain at some point in their post-amputation course.1 Typically, the pain is throbbing, stabbing, burning, or cramping, worse in the most distal portions of the phantom limb (e.g. toes), starts shortly after surgery, and can decrease slightly over time. Some patients describe shortening of the phantom limb over time also known as telescoping. The pain may be exacerbated by psychological factors such as stress, and depression, and physical factors such as pressure on the residual limb, and weather changes.2 Another cause of pain in the amputated limb is residual limb pain (RLP), or “stump” pain which happens in 43-76% of amputees. The pain is localized to the remaining portion of the limb and decreases in intensity and frequency over time. RLP can occur due to skin breakdown/wound dehiscence, infection, neuropathic pain, nerve entrapment, neuroma formation, surgical trauma, or prosthesis-induced (most common).3 Patients may also have phantom limb sensation, where they feel the missing limb, but the sensation is described as tingling or itchy but not painful. 

 

2. What is the pathophysiology of pain in an amputee?

Changes to the brain, spinal cord, and peripheral nerves following amputation are well documented. A primary mechanism of phantom pain is cortical reorganization, whereby neighboring neurons invade part of a deafferented cortex, corroborated by functional MRI findings.4 For example, cortical areas of the mouth can invade a cortical area previously responsible for the now amputated hand. By then stimulating the mouth, phantom limb sensations have been shown to occur.5 Studies have also provided a positive correlation between the level of phantom limb pain and somatosensory cortical reorganization.5,6

In the spinal cord, there is an increase in neural activity, expansion of the neuronal receptive field, and the nerves are hypersensitive due to an increase in N-methyl-D-aspartate and resulting sensitization to substance P, tachykinins, and neurokinins. In addition, inhibitory activity in the supraspinal centers is decreased.

Proximal severed peripheral nerves develop neuromas, which have more sodium channels, and result in spontaneous discharge.7 Similarly, this sprouting leads to the reorganization of the primary motor cortex seen in amputees, and sensory afferent nerves from the residual limb reinnervate areas of the cuneate nucleus region previously serving the amputated limb. The cuneate nucleus relays information to the somatosensory cortex, thus providing a mechanism by which stimulation of the stump skin can transmit sensory information to a phantom limb.

Psychological stress also plays a role in PLP. Amputees with PLP exhibit enhanced stress response compared to amputees without PLP which has been demonstrated at the cortical level using EEG.2,8 A different study revealed 44% of patients had a change in pain preceding a change in stress, and 37% had a change in stress precede a change in pain.9

 

3. What are the factors which make this patient at higher risk for PLP? What other factors increase the risk for pain in amputees?

Many risk factors have been shown to play a significant role in the development of PLP. These include bilateral amputation, lower limb amputation, proximal site of amputation, phantom sensations, residual limb pain, pain prior to the amputation, cause of amputation (elevated risk with diabetic etiology, acute thrombotic etiology), and post-amputation depression.1,10 Conversely, protective factors include the use of a prosthetic and increased time since the amputation.1,11

 

4. What perioperative strategies could be considered to prevent residual or phantom limb pain?

Perioperative and regional anesthesia may play a role in PLP prevention.12 Perioperative epidural local anesthetic, with or without additional analgesia, is promising for short-term PLP prevention; however long-term results are mixed. Possible adjuvants to perioperative epidurals include ketamine, opioids, and calcitonin. Perioperative perineural catheters for 3-30 days may also play a role in preventing PLP; however, their primary role is to reduce opioid use.

Several surgical approaches may prevent PLP including targeted muscle reinnervation (TMR), targeted nerve implantation (TNI), nerve coaptation, and regenerative peripheral nerve interface (RPNI).13 When a mixed or sensory nerve is transected, the proximal end can be coapted to the distal nerve end of a transected motor nerve (TMR), or the proximal end can be transferred and sutured to a secondary motor nerve (TNI). In nerve coaptation, the bifurcation of common peroneal and tibial nerve is identified, transected distally, and then sutured end to end and wrapped with a collagen nerve wrap. Finally. in RPNI, a major nerve is transected and the epimysial end is sutured to the epineurial end into a non-vascularized muscle graft, which is then placed distal to the incision and weight-bearing surfaces.

 

5. When should imaging be considered for this patient?

Imaging studies are used to identify an organic cause of pain in an amputee.14 X-rays of the residual limb can be used to identify osteomyelitis, bone spurs, aggressive edges, and heterotopic ossification. Ultrasound may be used to assess soft tissue abnormalities and superficial fluid collections, such as hematoma, seroma, or abscess.15 MRI should be considered if the pain origin is not identified, as it can demonstrate inflammatory changes, deeper fluid collections, traumatic bone lesions, and neuromas. If the patient has a prosthetic, which is thought to be the cause of the pain, video fluoroscopy can be performed to assess the prosthetic fit.

 

6. What rehabilitation approaches are useful for managing this patient’s pain?

Rehabilitative approaches are generally thought to target maladaptive cortical reorganization and include mind-body therapies, transcutaneous electrical nerve stimulation (TENS), acupuncture, and augmented or virtual reality.

Mind-body therapies that demonstrated some success with PLP include biofeedback (including mirror therapy (MT)), guided imagery, and hypnosis.16 In biofeedback, visual or auditory signals are used to learn control of physiologic processes such as heart rate, blood pressure, and muscle tension, and thus regulate the autonomic nervous system.16 MT specifically is the most effective type of biofeedback for PLP. In MT, the patient places a mirror between the amputated and intact limb and looks in the mirror while the intact limb moves, providing the illusion that the amputated limb is used and resulting in cortical reorganization. While expert consensus on MT for PLP is high, and case studies are generally positive; efficacy in trials and recent meta-analyses are mixed.17 Outside of MT, thermal and electromyography are commonly used types of biofeedback for PLP, but there is no expert consensus on their efficacy.16

Guided imagery uses vision, hearing, smell, taste, position, and touch to create healing mental images.16

Hypnosis is defined as a “state of inner absorption, concentration, and focused attention”, resulting in memory, mood, and perception changes.16 To date, there is some short-term benefit; however, more data are needed.

TENS uses pulsed electrical current to stimulate large-diameter A-beta afferents or small-diameter A-delta afferents to produce analgesia and reduce muscle spasms. Non-randomized studies found some benefit, but there are no large randomized controlled trials, and there is no expert consensus on the role of TENS in PLP.18

Acupuncture involves inserting 5-20 thin needles into specific points in the body for 10-20 minutes, to recover the natural flow of ‘Qi’ or energy. Its use may modulate pain perception and is used in various pain conditions. Data regarding acupuncture and PLP are limited, with two controlled studies demonstrating significant improvement in pain when doing auricular acupuncture and acupuncture on the contralateral limb.19

Augmented and virtual reality for PLP are emerging technologies, and function similarly to MT; however, amputees can use them at any time (including while walking). Current evidence is largely based on case-control and case series, and the pain tends to recur within hours after treatment.17

 

7. What medications are useful for the treatment of PLP and what are their side effects and special considerations for use?

Despite a continually increasing number of treatment strategies that have been proposed and trialed in the management of PLP, this condition has long remained a difficult one to treat.20 Some have hypothesized that this difficulty may be due to the multifactorial nature of PLP.21 However, challenges in studying the effectiveness of various treatments for PLP may further complicate the issue.22 For example, differences in the definitions of PLP, etiologies of PLP, duration since amputation, and assessments of what constitutes a significant improvement in PLP may all contribute to the currently existing ambiguous data.20,22 Still numerous treatment strategies, including many pharmacological agents, have been proposed.20,22,23

One Cochrane review of randomized and quasi-randomized controlled trials that compared pharmacologic interventions with placebo was initially completed in 2011 and then updated in 2016. In reviewing a total of 14 studies and 269 patients, the authors concluded that the overall efficacy of these medications remains inconclusive.23 Another systematic review that included case reports, anecdotes, clinical experience, open-label trials, pilot studies, retrospective studies, meta-analyses, and systematic reviews in addition to randomized controlled trials in the evaluation of pharmacological agents for PLP also concluded a lack of clear evidence to support any medication over another in the treatment of PLP.20,23

Given the unclear efficacy of all of these medications, careful consideration must be given to the patient’s past medical history/comorbidities, age, and already prescribed medications when attempting to employ any additional pharmacological agents in the treatment of PLP. Moreover, evaluation for any potential side effects and assessment of patient-reported benefit must be re-examined on a routine basis. To date, the strongest evidence for pharmacologic therapy in PLP exists for morphine (oral and intravenous), gabapentin, and ketamine (Table 1).

Morphine is an opioid medication that is thought to derive most of its analgesic effects from its affinity to the mu-opioid receptors in both the central and peripheral nervous systems but also binds to the kappa and delta opioid receptors.24 Most frequently, this mechanism can lead to the unwanted side effect of constipation. However, careful monitoring for some of the most frequently reported side effects, including sedation, respiratory depression, nausea/vomiting, urinary retention, pruritus, and lightheadedness/dizziness is required and may necessitate cessation of therapy.23,24 In the Cochrane review, morphine (both oral and intravenous) was effective for reducing short-term pain intensity compared with placebo (Level 2 evidence), and oral morphine was effective for up to one year (Level 2).20,23

Ketamine is a dissociative anesthetic that functions as an NMDA and glutamate receptor antagonist, in addition to possessing partial opioid mu receptor antagonism properties.25 While numerous potential adverse side effects can affect various body organs, the most commonly reported complications in those utilizing this for PLP include drowsiness, loss of consciousness, hallucinations, auditory and proprioceptive impairments, and insobriety.23,25 Perioperative IV ketamine and short-term ketamine were effective for short-term pain relief (Level 2).20

Lastly, gabapentin interacts with central voltage-gated calcium channels as a centrally-acting medication with voltage-gated to inhibit the release of presynaptic excitatory neurotransmitters.26 Particular evaluation for renal impairment must be considered when utilizing this medication. As compared to placebo in the treatment of PLP, the most commonly reported adverse side effects include somnolence, headaches, nausea, and dizziness.23 Gabapentin had mixed level 2 evidence to support its use for pain relief of up to six weeks.

Other medications that have been utilized in the treatment of PLP include but are not limited to tricyclic antidepressants (e.g., amitriptyline, doxepin), selective serotonin reuptake inhibitors (e.g., fluoxetine), serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine, milnacipran), anticonvulsants (e.g., pregabalin, topiramate, carbamazepam, and clonazepam, in addition to gabapentin), local anesthetics (e.g., lidocaine, mexiletine, ropivacaine, and bupivacaine), botulinum neurotoxins (e.g., botulinum toxin A), NMDA receptor antagonists (e.g., memantine, dextromethorphan, and methadone, in addition to ketamine), opioids (e.g., methadone which also possesses NMDA-receptor antagonism properties, and fentanyl, in addition to morphine), beta-blockers (e.g., propranolol), and hormonal agents (e.g., calcitonin).3,4 The specific mechanisms of action, dosing considerations, and potential side effects of all of these pharmacologic interventions are beyond the scope of this article.

 

MedicationMechanism of ActionDosingSide Effects
Gabapentin/Pregabalin26

Exact mechanism unknown, acts on voltage gated calcium channels
Gabapentin: typically 300mg at night, increasing frequency to three times per day for a max dose 4,800mg per day; consideration for renal function
Pregabalin: 50mg three times per day, up to 300mg per day
Fatigue, dizziness, headache, nausea; requires a taper
Morphine24Acts on mu opioid receptors in both the central and peripheral nervous systems, binds to the kappa and delta opioid receptorsVariable depending on mix of immediate and extended releaseConstipation, sedation, respiratory depression, nausea/vomiting, urinary retention, pruritus, and lightheadedness/dizziness
Ketamine25NMDA and glutamate receptor antagonist, partial opioid mu receptor antagonistVariable, can be oral or IV, refer to consensus27Drowsiness, loss of consciousness, hallucinations, auditory and proprioceptive impairments, and insobriety


Table 1: Summary of Effective Medications Used for Phantom Limb Pain

 

8. What basic interventions could be considered for this patient? 


There is a large amount of variability in the use of sodium channel blockers as it pertains to PLP.20,28 As compared to some of the other therapeutic modalities, these perineural or epidural interventions attempt to prevent PLP.21 Some have studied the use of sodium channel blockers alone, whereas others have combined these anesthetics with opioids or alpha antagonists. In addition, the timing and duration of these blocks varies widely. Classically these interventions are started before the amputation but may be continued from anywhere between a few days to a few months post-operatively.20,28 Some studies suggest potential benefits for acute pain, whereas others note no improvement in the development of PLP as compared to alternative therapies.22

While the literature is limited, lumbar sympathetic blocks may represent an additional interventional option for this patient. Given the suspicion that sympathetic hyperactivity may contribute to PLP, it is theorized that lumbar sympathetic blocks may be beneficial.29 One small case series evaluated the efficacy of lumbar sympathetic blocks versus sham needle placement and found reductions in PLP at three-month follow-up. However, further research is required to further assess the efficacy of this intervention.29
 
Pulsed radiofrequency ablation can also be considered for this patient. While there is currently a lack of sham interventions, pulsed radiofrequency ablation has demonstrated improvement in case series/case reports previously.30,31

 

9. What advanced interventions can be considered to treat PLP? 

For those cases of PLP refractory to conservative treatment strategies, more advanced interventions may be considered. First utilized for PLP in 1969, spinal cord stimulation (SCS) represents one of the oldest advanced interventions to treat PLP.32 In a prior systematic review of twelve studies that utilized SCS to treat PLP in both upper and lower extremity PLP, seven demonstrated clinically significant improvement while the other five did reveal any significant pain relief. The authors anticipated that with continued innovation in SCS, this modality may offer further benefit in the treatment of PLP in the future. However, there are concerns that SCS may not offer as much benefit in the long-term treatment of PLP.
 
Another advanced intervention that has been utilized in the treatment of PLP is dorsal root ganglion (DRG) stimulation.33 Proponents of DRG stimulation have argued that it offers several advantages over SCS in the treatment of PLP, in part due to its ability to target the primary sensory neurons that are theorized to be responsible for PLP. One review of eight patients trialing DRG neuromodulation systems for PLP found improvement in patient-reported pain, as well as in quality of life and functional capacity.
 
Peripheral nerve stimulation (PNS) has also recently been gaining popularity in the treatment of PLP.34 While the literature is currently limited, a small case series demonstrated pain relief and improved patient functionality for patients with PLP. However, the authors note that this benefit may be short-lived, with the pain returning within a month of PNS device removal. Similar to the above advanced interventions, further research is needed to assess not only the potential benefit this modality may offer to patients but also to evaluate factors within patients that may benefit most from this emerging neuromodulation treatment.

 

References

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