**6. Pharmacology**

### **6.1 Opioids**

*Pain Management - Practices, Novel Therapies and Bioactives*

to opioid therapy in the immediate post-operative period. Thorough patient education and compassionate counseling also play a key role in developing a team

The current standard of care is pre-operative nerve blockade to prevent peripheral

sensitization leading to future onset of phantom limb pain. Successful outcomes necessitate effective communication between the surgeon, anesthesiologist, and the various teams involved in the post-operative rehabilitation of the patient. A consultation with the Acute Pain Service or similar entity that performs peripheral nerve blockade pre-operatively and then follows the patient during their post-operative inpatient course is an important factor in the success in early prevention of acute and

Most patients that arrive for amputations should be evaluated to receive preoperative peripheral nerve blocks. If this cannot be done pre-operatively, patients can be evaluated post-operatively for a nerve block. If patients do not require post-operative anti-coagulation that will preclude a continuous peripheral nerve catheter, this would be the preferred nerve block for these patients as this will help with prevention phantom limb pain and chronic post-operative pain [3]. This can be utilized for 3–5 days. Continuous nerve catheter infusions have been found to decrease post-operative morphine requirements [21]. However, in addition, there are other factors that may preclude continuous peripheral nerve catheter placement such as infection, and patient factors. If this is the case, single shot peripheral nerve blocks may be utilized. Interestingly, a systematic review and meta-analysis found no difference in pain scores at 24 hours between patients that received a nerve block and those that did not [22]. However, this study did not look at chronic pain in these patients which is the important component that these nerve blocks are used for [9]. It is important to understand the anatomy of the amputation site to have successful nerve block placement. For example, a below the knee amputation will rely heavily on a sciatic nerve blockade whereas an above the knee amputation will need blockade of both femoral and sciatic nerves for successful pain control and help with peripheral sensitization for the patient [9]. For upper extremity amputations, a forearm

relationship with the patient [19, 20]. See **Figure 2** for full protocol.

**5. Nerve blockade**

*Protocol for amputation pain management.*

**Figure 2.**

chronic pain for these patients.

**38**

Opioids remain a favored therapy for pain after surgery. They bind to Mu receptors in peripheral and central nerves as an agonist fashion to produce analgesia. They also can affect phantom limb pain by reducing cortical reorganization [10]. There is a wide variety to choose from post-operatively as they come in intravenous and oral formulation. Usually initially a parenteral opioid therapy with a patient-controlled analgesia (PCA) is started on post-operative day (POD) zero. Once the patient is tolerating a diet, the PCA is weaned down incrementally and oral opioid therapy is instituted. For opioid tolerant patients, we attempt to calculate their total daily morphine equivalent requirement and base our starting oral dose based on that. The goal is to wean off the PCA completely by 48 hours, coinciding with the discontinuation of other intravenous infusion [10].

#### **6.2 N-Methyl-D-Aspartate (NMDA) Receptor Antagonists**

Ketamine has been studied for post-operative pain. It has been shown that the use of this medication lowers the opioid requirements and reverses opioid tolerance needed for acute post-operative pain [24]. Ketamine is a noncompetitive NMDA receptor antagonist that targets primarily in the brain and spinal cord. The NMDA receptor is important for synaptic plasticity, central sensitization, amplification of pain signals and opioid tolerance. For amputations, it lowers the dorsal horn sensitization and stops the events that may lead to phantom limb pain and residual limb pain. Important to note, it will not prevent phantom limb pain but will reduce risks of phantom limb pain and residual limb pain [9]. Ketamine has also been shown to have anti-inflammatory properties which may be effective in the early pre-operative phase. Ketamine infusions can be started in the operating room and continued for 2–3 days post-operatively. Studies show low does ketamine infusions do reduce opioids immediately post-op but there was not a significant reduction in immediate post op pain ratings [2, 3, 10].

#### **6.3 Gabapentinoids**

Gabapentin and pregabalin are both anti-convulsant that inhibit alpha 2-delta subunit of voltage-gated calcium channels. They are structural like GABA

neurotransmitter, but they are unable to bind to any GABA receptors. In addition to the use with seizures, it has been used for chronic pain, especially neuropathic in nature. Dosages must be titrated slowly, and results are not seen immediately. These doses also must be adjusted for patients with impaired renal function with the help of a pharmacist [25, 26]. However, some studies claim that its efficacy to treat phantom limb pain is inconclusive and limited by dose dependent side effects like somnolence and dizziness [2]. There are other studies more recently that show promise of administration of gabapentinoids for reducing chronic post-surgical pain and this can be exploited to amputees as well [3, 9, 10].

#### **6.4 Acetaminophen**

Acetaminophen's exact mechanism of action is not well understood, but it is thought to reduce the production of prostaglandins in the brain. Prostaglandins are chemicals that cause inflammation and swelling. Acetaminophen relieves pain by elevating the pain threshold, that is, by requiring a greater amount of pain to develop before a person feels it. Acetaminophen administration to amputation patients will help with inflammation and an adjunct to help with post-surgical nociceptive pain, which has been shown to decrease opioid requirements. Acetaminophen dosages will be lowered in patients with pre-existing liver disease [27]. This will be the most beneficial in the early pre-operative phase. It may be especially beneficially to start prior to the amputation as part of a pre-emptive analgesia. This is thought to protect the central nervous system from noxious insults which result in the patient getting hyperalgesia and allodynia [10, 28].

#### **6.5 NSAIDs**

NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (COX-1 or COX-2). By blocking the Cox enzymes, many prostaglandins are not made. This means that there is less swelling and less pain. Most NSAIDs block both Cox-1 and Cox-2 enzymes. For pain, this specifically looks at enzymes that work with prostaglandins for inflammation. Like acetaminophen, these medications work well in the acute perioperative phase for nociceptive pain and reducing opioid requirements. Their use can be limited due to post-operative bleeding concerns. Usually these medications do not help with chronic post amputation pain or phantom limb pain. A short course may be suitable for some patients that have normal renal function; however, we do not advocate for chronic NSAID therapy due to the risks of gastrointestinal bleeding and renal toxicity [10, 23, 29].

#### **6.6 Muscle relaxants**

As discussed earlier, acute post-operative pain can have spasmodic pain proximal to the stump site, likely due to tissue inflammation. This can also be present with residual limb pain in some patients. There are a variety of muscle relaxants that can be tried for a short period of time [30]. If the patient is on opioids, would be cautious of adding a benzodiazepine for muscle relaxant. There is a lack of adequate literature supporting the use of muscle relaxants for post amputation pain.

#### **6.7 Tri-cyclic antidepressants and selective norepinephrine reuptake inhibitors**

Anti-depressants are commonly prescribed for chronic neuropathic pain and coexisting depression that accompanies it. These medications work by inhibiting serotonin-epinephrine uptake blockade, NMDA receptor antagonism and sodium

**41**

**8. Conclusions**

13. Neurolysis

**Table 2.**

*Amputation Pain Management*

limb pain [9, 10, 31].

**6.8 Calcitonin**

*DOI: http://dx.doi.org/10.5772/intechopen.93846*

of phantom limb pain with its use [9].

**7. Therapeutic modalities**

These are summarized in **Table 2**.

1. Desensitization techniques

8. Peripheral nerve stimulation 9. Prolonged peripheral nerve blockade

10. Sympathetic nerve blocks 11. Deep brain stimulators 12. Spinal cord stimulators

*Therapeutic modalities for chronic amputee limb pain.*

2. Mirror therapy 3. Massage 4. TENs 5. Exercise

6. Hot/cold therapy 7. Biofeedback

channel blockade. These medications have not been shown to work effectively in phantom limb pain in studies. These are not usually done in the perioperative setting as they require careful titration over weeks to months which is better done as outpatient therapy. Side effects of opioids and other modalities may warrant a small dose trial in the perioperative setting to help with uncontrolled acute or phantom

Calcitonin is a hormone secreted by thyroid gland in parafollicular cells. Unlike

synthetic forms of this used for chronic pain syndromes. The exact pain mechanism of action is unknown. There are mixed results of phantom limb pain [10]. The greatest benefit has been shown when it is administered early in the perioperative period; usually within the first 7 days [32]. There are reports of complete resolution

There are many additional modalities that may be of benefit to amputee patients after the initial perioperative period to help with phantom limb pain and residual limb pain. Many of these involve experienced providers and therapists [2, 10, 12, 33–36].

As patient's present for amputations, it is important to remember the care for these patients needs to be multi-disciplinary to prevent chronic pain. If perioperative pain plans are developed early and worked on as a team, the patient will benefit the most and have the best chance for success at not having long-term phantom limb pain and/or residual limb pain which adversely impact their quality of life.

the parathyroid hormone, its job is to reduce calcium in the blood. There are

#### *Amputation Pain Management DOI: http://dx.doi.org/10.5772/intechopen.93846*

channel blockade. These medications have not been shown to work effectively in phantom limb pain in studies. These are not usually done in the perioperative setting as they require careful titration over weeks to months which is better done as outpatient therapy. Side effects of opioids and other modalities may warrant a small dose trial in the perioperative setting to help with uncontrolled acute or phantom limb pain [9, 10, 31].
