A 60-year-old male with a history of a right knee injury resulting in osteoarthritis and subsequent right total knee replacement continues to suffer from right knee pain. His pain has been refractory to physical therapy, opioids including morphine sustained release, and gabapentin. His past medical history is significant for hypertension and depression. His mood has been affected by his chronic pain issues, and he was recently placed on duloxetine with minimal benefit. He continues to suffer from right knee pain, which he describes as aching, throbbing pain, with occasional severe spasms in his calves. He presents to his primary care physician's office for further treatment options regarding his pain.
The patient has significant pain that has not responded to conservative treatment with opioids, physical therapy, anticonvulsants, and antidepressants. At this time, there is no mention of other adjuvant analgesics for his pain symptoms, and therefore the treating provider should address and treat as necessary.
The traditional analgesics are nonopioids (for example, NSAIDs) and opioids. Adjuvant analgesics are drugs in which the primary indications are for conditions other than pain, but are being used in the management of chronic pain. In some clinical settings, such as in patients with postherpetic neuralgia, trigeminal neuralgia, and painful polyneuropathies, they are accepted as a first-line drug. In the analgesic ladder, best pain relief may be obtained if all components of the ladder are used simultaneously, in the sense that one analgesic for one drug class adds to the analgesia provided by another drug class. Adjuvant analgesics include antidepressants (discussed in Chapter 25), anticonvulsants (discussed in Chapter 26), local anesthetics, alpha-2 adrenergic agonists, N-methyl-d-aspartate (NMDA) receptor antagonists, and topical agents. Including these medications in an analgesic regimen may prove to be beneficial for pain control.
Local anesthetics (LA) in the form of IV, oral, or topical agents (creams, gels, patches), have been used for years for treatment of various chronic pain conditions. These include lidocaine, bupivacaine, and mexiletine.
LAs belong to the anti-arrhythmic group of medications and are used to treat arrhythmias of the heart, but have been used in patients experiencing refractory pain. They adhere to peripheral nerves and reduce pain signals carried from the peripheral nervous system to the central nervous systemand brain. Mexiletine, in particular, has efficacy in the treatment of muscle stiffness disorders such as myotonia congenita or myotonic dystrophies. Mexiletine is used experimentally to treat pain associated with different kinds of peripheral neuropathy and has not been FDA approved.
ALPHA-2 ADRENERGIC AGONISTS
Alpha-2 adrenoreceptors (A2A) are located in primary afferent terminals, neurons in the superficial lamina of the spinal cord, and within several brainstem nuclei. Tizanadine and clonidine have utility as a pain reliever.
Clonidine produces analgesia at alpha adrenoreceptors in the spinal cord; it blocks conduction of C and A delta pain fibers, increases potassium conductance, and intensifies conduction blockade of local anesthetic. It is possible to achieve analgesia from systemic, epidural, or intrathecal administration of clonidine. Side effects include hypotension secondary to reduced sympathetic drive, bradycardia, and sedation. Clonidine has been used to treat neuropathic pain that is not responding to other treatment or therapy.
Tizanidine has been FDA approved as a muscle relaxant. It is used to treat spasms, cramping, and tightness of muscle caused by various conditions including multiple sclerosis, spasticity, back pain, or other injuries to the central nervous system. Side effects include hypotension and liver damage, therefore, patients treated with this drug should have baseline and regular liver function tests (LFTs) within the first six months of treatment. Tizanidine can cause sedation and has a potential to interact with other CNS depressants.
NMDA RECEPTOR ANTAGONISTS
NMDA is one of the newly discovered modulators in the spinal cord. The NMDA receptors function to cause changes in the hyperexcitability of the dorsal horn neuron, resulting in allodynia and hyperalgesia. Allodynia is pain produced by a non-noxious stimulus, and hyperalgesia is exacerbated pain produced by a noxious stimuli. NMDA receptor antagonists are useful in reducing opiate tolerance and hyperalgesia related to various painful conditions.
Ketamine is an anesthetic agent that blocks NMDA receptors and inhibits allodynia and hyperalgesia. Ketamine can be given by multiple routes including IV, IM, subcutaneous, oral, and transdermal. Orally administered ketamine undergoes extensive first-pass metabolism. Low-dose ketamine is recommended for its potential effectiveness in the treatment of complex regional pain syndrome according to a retrospective review published in Pain Medicine in 2004. Although low-dose ketamine therapy is established as a generally safe procedure, there are side effects in some patients which included hallucinations, dizziness, lightheadedness, and nausea.
Dextromethorphan is an oral antitussive that blocks NMDA receptors. It is associated with serotonin syndrome symptoms, which can include confusion, excitement, nervousness, restlessness, irritability, nausea, vomiting, and dysarthria. Dextromethorphan is also being studied as a possible treatment for neuropathic and fibromyalgia associated pain. It should be used with caution in patients taking monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly due to a buildup of excessive amounts of serotonin in the body.
Topical agents can be used at the site of pain to alleviate symptoms. There have been multiple agents that have been used and compounded for treatment, for example, lidocaine, prilocaine, capsaicin, nonsteroidal anti-inflammatories, doxepin, amitriptyline, baclofen, gabapentin, ketamine, methyl salicylate (which can increase coumadin effects), and others.
A 5% lidocaine patch has been used for pain reduction in patients with postherpetic neuralgia. It is prescribed as 12 hours on and 12 hours off with a maximum of three patches at a time secondary to its toxicity. The patch can be cut to fit in a well-circumscribed area.
Capsaicin causes sensory nerve C-fibers to deplete their substance P. It is available as a topical cream (0.025% or 0.075%) which can be used 4 to 5 times daily. Most patients begin to see results within a few weeks of treatment. Its limited usefulness occurs secondary to initial burning upon application and subsequent intolerance by the patients. The frequency, treatments, and the painful side effect limit the compliance of this particular medication.
Key Points to Remember
• Adjuvant agents have shown efficacy for analgesia and are often part of the treatment for patients with chronic pain.
• Tizanadine can cause liver dysfunction, therefore LFTs should be monitored.
• Dextromethorphan should be used with caution in patients taking monoamine oxidase inhibitors (MAOIs) or serotonin reuptake inhibitors, due to the potential for serotonin syndrome.
• When choosing an adjuvant drug, consider the patient's past medical history and the medication's side-effect profile.
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