Pain Management

Inflammatory Pain

In contrast to nociceptive pain, inflammatory pain occurs in response to significant tissue damage and can cause physiologic changes in the nervous system that potentiate pain. This potentiation can occur in 3 different ways: 1) Proinflammatory mediators released by damaged tissue can lower the threshold of primary sensory neurons, causing normally innocuous stimuli to become painful. This process is called peripheral sensitization 2) Inflammation can potentiate pain by altering the properties and functions of neurons, a phenomenon referred to as a phenotypic switch. 3) Inflammation can increase the excitability and responsiveness of neurons in the CNS, a process called central sensitization. The end result of each of these 3 processes is an exaggerated pain response. Inflammatory pain can be acute (eg, pain occurring after surgery) or ongoing (eg, pain associated with a chronic inflammatory disease, such as rheumatoid arthritis).

Neuropathic and Functional Pain

Neuropathic pain may result from a lesion to the peripheral nervous system, as in diabetic or AIDS polyneuropathy, postherpetic neuralgia, or lumbar radiculopathy, or from a lesion to the central nervous system, as in spinal cord injury, multiple sclerosis, or stroke. Neuropathic pain shares a few mechanistic similarities with inflammatory pain, but nerve injury—related symptoms are the key features distinguishing neuropathic from inflammatory pain.

In contrast to neuropathic pain, for which an underlying cause is identifiable, functional pain is pain that lacks a recognizable cause, Functional pain has no clear peripheral or central pathology, yet the patient experiences persistent pain. Examples of functional pain include the pain associated with irritable bowel syndrome, cancer, and tension or migraine headaches.

Mechanisms of Pain

Nociception

The mechanism of nociception has been thoroughly studied. Noxious stimuli such as extreme temperature, acidity, and mechanical force activate specific receptors located at the peripheral terminals of unmyelinated C-fibers and thinly myelinated M-fiber nociceptors. Activation of these receptors causes specific transducer proteins to depolarize the membrane. The resultant action potential is transmitted via the action of voltage-gated sodium channels from the periphery to the dorsal horn of the spinal cord and then to the brain, where it is processed and interpreted as a painful sensation.

Peripheral Sensitization

In response to tissue damage and inflammation, nociceptor function is significantly modified through the action of several inflammatory mediators including PGs Injured tissue releases multiple chemical mediators that activate an enzymatic cascade resulting in increased PG synthesis and release. The PG biosynthetic pathway begins with arachidonic acid which is released from cell membranes by the action of phospholipase A2 enzymes Arachidonic acid is converted into the PG precursor molecules prostaglandin G2 and prostaglandin H2 through the action of COX enzymes. Tissue specific syntheses subsequently convert these intermediaries into various PGs and thromboxanes. PGs exert their effects by acting on G protein—coupled receptors located on the peripheral terminal thereby initiating an intracellular signal transduction cascade.

Clinical Evaluation

Diagnosis of neuropathic pain is difficult because patients who present to a clinician often have diverse causes of pain and a wide spectrum of signs and symptoms. When a patient with pain is evaluated, the clinician should characterize the timing and mechanism of the initial injury. Another important aspect of the clinical evaluation is performance of a pain assessment. The patient should be asked to describe the location of the pain, its quality and intensity, when it began, and what factors aggravate or alleviate the sensation. Pain sensations common to patients with neuropathic pain are often described as stabbing, aching, burning, shooting, pricking, or electric shock—like. Visual or numerical scales may be useful tools for measuring a patient’s perception of pain intensity. Several questionnaires have been developed for measuring and characterizing neuropathic pain.

Diagnosis of Neuropathic Pain

A careful sensory examination aids the clinician in determining the location and distribution of the patient’s pain; it also suggests which major nerves are involved and indicates whether the patient’s pain is stimulus dependent or stimulus independent.
No single diagnostic tool can confirm a clinician’s impression that a patient suffers from neuropathic pain. Common diagnostic tools such as electromyography and nerve conduction velocity are capable of assessing large nerve fiber function, but they cannot assess the function of smaller fibers involved in pain sensation. Neuropathic pain cannot be excluded on the basis of normal electrodiagnostic studies.

Central Sensitization Caused by Nociceptor Hyperactivity

Peripheral nerve hyperactivity causes primary afferent sensory fibers to release neurotransmitters and peptides that increase the excitability of spinal cord neurons. Consequently, release of glutamate and substance P disrupts the balance between inhibitory (y-aminobutyric acid) and excitatory (glutamate) neurotransmitters. Substance P releases the magnesium channel block from the N-methyl-d-aspartate (NMDA) receptor, allowing glutamate to bind. Glutamate activation of the NMDA receptor results in calcium ion influx, which elicits various cellular changes that potentiate pain. Thus, sensitization of peripheral nerves can cause additional changes within the spinal cord, resulting in hyperexcitability of central neurons, or central sensitization.

Solutions for Effective Pain Management

It is possible for clinicians to overcome many of the problems associated with pain management. JCAHO guidelines call on organizations and healthcare facilities to: 1) recognize that patients have the right to receive appropriate pain assessment and management; 2) properly screen for and assess the nature and intensity of a patient’s pain; 3) record pain assessment data in a manner that will guarantee reassessment and follow-up; 4) make certain that staff members are educated and competent in assessing and managing pain; 5) establish policies and procedures that support appropriate prescribing or ordering of pain medications; 6) ensure that pain does not impede a patient’s rehabilitation; 7) educate patients and families about the importance of effective pain management; 8) address patient needs for managing symptoms in discharge planning; and 9) collect and monitor data on the effectiveness of pain management. Programs to improve the treatment of pain should include raising a red flag for unrelieved pain to attract a physician’s attention, providing readily available information on analgesics when orders are typically written, and creating a patient-centered environment in which patients can readily communicate their pain to healthcare professionals.

Pharmacologic approaches

Tramadol

Tramadol is a nonopioid, nonnarcotic, centrally-acting synthetic analgesic. In randomized, double-blind, placebo-controlled clinical trials, tramadol provided relief of pain associated with polyneuropathy and Peripheral Diabetic Neuropathy (PDN). Tramadol (200 to 400 mg per day) is more effective than placebo in reducing paresthesia, touch-evoked pain, and allodynia scores. The most common adverse events associated with tramadol administration include dizziness, nausea, constipation, somnolence, and orthostatic hypotension, however, these adverse events may occur less frequently if doses are increased slowly over time.
Although rare, the risk of seizure has been reported with tramadol, as has an increased risk in patients taking concomitant selective serotonin reuptake inhibitors (SSRIs), TCAs, and opioids.

Opioids

Opioids exert their analgesic effects by binding to 1 or more opioid receptors expressed in the spinal cord and brain. Analysis of receptor subtypes has indicated that each receptor plays a distinct role in pain inhibition. The various analgesic effects induced by opioids are primarily due to different affinities for each receptor subtype. Clinical trials have demonstrated that opioids provide effective pain relief for patients with PDN. In a randomized, placebo-controlled clinical trial of patients with moderate to severe pain due to PDN, controlled-release oxycodone (up to 60 mg per day) significantly reduced the overall average daily pain intensity score compared with placebo. In a second study of PHN, patients indicated a preference for opioids (controlled-release morphine or methadone) over tricyclic antidepressants (TCAs: nortriptyline or desipramine), even though pain relief measurements were similar between treatments, and adverse events were increased among patients who took opioids. Levorphanol, a synthetic opioid compound, has demonstrated efficacy against neuropathic pain in patients refractory to conventional treatment.

Tricyclic Antidepressants

TCAs were the first class of drugs found to be efficacious for the management of neuropathic pain in placebo-controlled trials. Initially, amitriptyline was the most commonly used antidepressant for the treatment of neuropathic pain, but its relatively poor tolerability profile, primarily due to its anticholinergic adverse effects, has limited its clinical usefulness. Nortriptyline, the major metabolite of amitriptyline, was subsequently found to have comparable efficacy with improved tolerability. However, TCAs are associated with serious adverse events, including cardiac conduction abnormalities, and therefore must be used with caution in patients with a history of cardiovascular disease.

Gabapentin

Gabapentin, an anticonvulsant approved for the management of PHN. In patients with PHN or peripheral diabetic neuropathy (PDN), gabapentin (up to 3,600 mg per day) significantly reduced average daily pain scores compared with those observed in the placebo arm. In addition to pain relief, patients who received gabapentin experienced improvements in their quality of life, sleep, and mood. Although clinical trials used doses up to 3,600 mg per day.

Second-Line Therapies

Patients with neuropathic pain who do not respond well to initial single or combination therapy may benefit from a number of other drugs that are considered second-line medications.

Carbamazepine

Carbamazepine is one such therapy, which is currently Food and Drug Administration (FDA) approved for the treatment of trigeminal neuralgia.

Lamotrigine

Lamotrigine, an antiepileptic agent, has also shown efficacy in treating neuropathic pain; however, drug-associated adverse events may limit its clinical usefulness.

Oxcarbazepine

Oxcarbazepine, another antiepileptic drug, has been shown to alleviate neuropathic pain. It has shown efficacy in patients with trigeminal neuralgia, including those with disease refractory to carbamazepine, suggesting that oxcarbazepine may offer a suitable alternative to carbamazepine therapy.

SSRIs have been studied as an alternative to TCAs for the treatment of painful neuropathy. Clinical trial results indicate that bupropion, citalopram, paroxetine, and venlafaxine can be recommended as second-line agents for patients who have not responded to a trial of TCAs. SSRIs may reduce the risk for adverse events and are typically better tolerated than TCAs.

Combination Therapy

Because of the diverse causes that contribute to neuropathic pain, it is not surprising that responses to medications vary widely among patients. Partial responses to single medications are common, and combination treatment with 2 or more first-line medications can be considered.

Topical Local Anesthetics

A number of randomized, double-blind, vehicle-controlled clinical trials have demonstrated the efficacy of the 5% lidocaine patch for treatment of postherpetic neuralgia (PHN). It is important to note that statistically significant reductions in pain intensity scores were observed as early as 30 minutes after patch application. More recently, investigators assessed the efficacy of the 5% lidocaine patch in reducing the most common pain qualities reported by patients with neuropathic pain according to the neuropathic pain scale.

TOPICAL TREATMENTS FOR PAIN

Topical analgesics exert their analgesic benefit locally and without significant systemic absorption. They have been shown to provide pain relief in a variety of acute and chronic pain disorders. The mechanism of the topical analgesic is unique to the specific medication. Most of the topical analgesic compounds or “targeted peripheral analgesics” significant alter the pain process. The use of these topical agents is associated with fewer side effects and is better tolerated than oral agents. Some of the topical agents in use in our practice are the following:

Lidocaine

Lidocaine patches (5%), are well tolerated and their activity last al least 24 hrs. It is currently available for use in medical offices in the treatment of neuropathic pains.

EMLA

EMLA cream (eutectic mixture of local anesthetics, 2.5% lidocaine/2.5% prilocaine) can causes analgesia and anesthesia where is applied.

Zonalon

Zonalon (doxepin hydrochloride) is a tricyclic anti-depressants used locally as analgesic cream. It is also used in the treatment of the eczema-associated pruritus. It have some topical analgesic properties.

Vanifloids

Currently, capsaicin is the only available commercial preparation in this category. It is potent for naturopathic and joint pain, and lack of systemic absorption allows its use with systemic analgesic regimens. Capsaicin is difficult to use, requires multiple daily applications, is poorly tolerated because it burns on application, and is aesthetically unpleasant for some patients. The development of related compounds with improved tolerability is anticipated in the future. The capsaicin strengths are 0.025 and 0.075%. They are used in the neuropathic pain and the pain associated to diabetic neuropathy. In same cases the use of Capsaicin (0.075%) with Doxepin (3.3%) cream has showed significant released of pain associated to neuropathy.

Several combinations of active medications are currently in use in our practice to relieve neuropathic and myofacial pains. Significant analgesic effect has been obtained with the use of 4% aminotriptiline/2% ketamine creams with clonidine, aminotrytiline, etc.

Dihydroergotamine (DHE), available in several formulations, is effective in the treatment of migraine because of its serotonin (5-HT) 1D—receptor agonist properties. It is, however, contraindicated in patients with vascular disease, Early treatment of migraine is critical because it results in minimal disability and high rates of pain-free outcome. Although most patients with migraine wait to treat, early intervention (preferably within 20 to 30 minutes) prevents the development of central sensitization and cutaneous allodynia.

NMDA-Ca Channel blocker is a combination of ketamine (5-10%) in PLO, Dextgromethotphan 10% in PLO, Orphenadrine 10% in PLO and amantidine 10-20% tid.

AMPA-Na Channel blocker is a combination of Gabapentin (anti-convulsivant) 6-10% in PLO tid, Carbamazepine 10% in PLO and Lidocaine (5-10%) in PLO tid (may use Mexilitine 2% in PLO instead Lidocaine).

Alpha II-Agonist. The use of Clonididne 0.2% in PLO tid has shown benefit in comparison with the prior compounds.

GABA-Agonist: Baclofen 2% PLO tid.