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Articles  |   November 2007
Managing Neuropathic Pain
Author Notes
  • Dr Galluzzi is on the speakers bureaus of Eisai, Pfizer Inc, and Purdue Pharma LP. 
  • Address correspondence to Katherine E. Galluzzi, DO, CMD, FACOFP dist, Professor and Chair, Department of Geriatric Medicine, Philadelphia College of Osteopathic Medicine, 4190 City Ave, Suite 315, Philadelphia, PA 19131-1633. E-mail: katherineg@pcom.edu 
Article Information
Pain Management/Palliative Care
Articles   |   November 2007
Managing Neuropathic Pain
The Journal of the American Osteopathic Association, November 2007, Vol. 107, ES39-ES48. doi:
The Journal of the American Osteopathic Association, November 2007, Vol. 107, ES39-ES48. doi:
Abstract

Pain may be the most common reason patients seek treatment from physicians. When persistent and unrelieved, pain can frustrate both the person suffering with this condition and the physician trying to alleviate it. Relief from such discomfort may be particularly difficult to achieve and fraught with misconceptions. Treatment usually requires trials of physical, pharmacologic, and surgical interventions to achieve resolution. In cases that remain insoluble, patients must accept partial relief and seek adaptive strategies.

Sources of persistent pain may be nociceptive or neuropathic. Both utilize the same nerve pathways for transmission, but significant physiologic differences exist in mechanisms through which these painful stimuli are biologically processed and resolved. Nociceptive pain resulting from a known or obvious source (eg, trauma, cancer metastasis, ischemia, arthritis) is often easy to identify. Neuropathic pain, however, may occur in the absence of an identifiable precipitating cause. Physicians must remain alert to differences in presentation and course of neuropathic pain syndromes, some of which may be subtle or unusual.

The International Association for the Study of Pain defines neuropathic pain as “initiated or caused by a primary lesion or dysfunction in the nervous system” and due to disordered peripheral or central nerves.1 This disorder can be caused by compression, transection, infiltration, ischemia, or metabolic injury to neuronal cell bodies, or in combination. Neuropathic pain may be classified as either peripheral or deafferentation (central) in origin.2 Examples of the former include diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), antineoplastic therapy–induced or HIV-induced sensory neuropathy, tumor infiltration neuropathy, phantom limb pain, postmastectomy pain, complex regional pain syndromes (reflex sympathetic dystrophy), and trigeminal neuralgia. Deafferentation syndromes resulting in neuropathic pain include multiple sclerosis, spinal cord injury, central poststroke pain, and Parkinson disease. 
Bennett3 provided incidence estimates of common types of neuropathic pain and concluded that if neuropathic low back pain is included in the total, approximately 3.8 million individuals in the United States suffer from this disorder. Bowsher 4 calculated that as many as 1 million patients with PHN reside here. Such painful conditions are likely to increase as the population grows older and age-related disorders such as herpes zoster, diabetes mellitus, cerebrovascular accidents, Parkinson disease, and cancer—diseases of aging—develop. 
Diabetic peripheral neuropathy, second only to low back pain–associated neuropathy, is estimated to account for 600 cases per 100,000 (Table 1); this disorder is certain to increase as the population of citizens with diabetes mellitus also continues to expand. 
Table 1
Estimated Prevalence of Neuropathic Pain in the United States

Condition

No. per 100,000
□ Diabetic peripheral neuropathy600
□ Postherpetic neuralgia 500
□ Cancer-associated200
□ Spinal cord injury 120
□ Causalgia and reflex sympathetic dystrophy100
□ Multiple sclerosis 50
□ Phantom pain50
□ Poststroke pain 30
□ HIV-associated15
□ Trigeminal neuralgia (tic douloureux) 15
□ Low back pain—associated2,100
Total (excluding back pain) 1,680 M
Total (including back pain)3,780 M
 * Based on population of 270 million.
 Source: Bennett GJ. Neuropathic pain: new insights, new interventions.Hosp Pract (Off Ed). October 15, 1998;33(10):95-98, 101-104, 107-110 passim.
Table 1
Estimated Prevalence of Neuropathic Pain in the United States

Condition

No. per 100,000
□ Diabetic peripheral neuropathy600
□ Postherpetic neuralgia 500
□ Cancer-associated200
□ Spinal cord injury 120
□ Causalgia and reflex sympathetic dystrophy100
□ Multiple sclerosis 50
□ Phantom pain50
□ Poststroke pain 30
□ HIV-associated15
□ Trigeminal neuralgia (tic douloureux) 15
□ Low back pain—associated2,100
Total (excluding back pain) 1,680 M
Total (including back pain)3,780 M
 * Based on population of 270 million.
 Source: Bennett GJ. Neuropathic pain: new insights, new interventions.Hosp Pract (Off Ed). October 15, 1998;33(10):95-98, 101-104, 107-110 passim.
×
Neuropathic Versus Nociceptive Pain
Response to an acute painful stimulus is an important adaptive mechanism that protects a person from further injury. Considering characteristics that nociceptive and neuropathic pain have in common will help clarify their differences. Pain signals resulting from noxious stimuli (wounds, thermal or inflammatory insults) are converted into electrical impulses within tissue nociceptors whose cell bodies are found in dorsal root ganglions; both nociceptive and neuropathic pain signals utilize the same pain pathways. 
Information regarding intensity, quality, and location of pain is conveyed to the sensory cortex from the somatosensory thalamus. The central nervous system (CNS) utilizes descending inhibitory pathways via the dorsolateral fasciculus (Lissauer's tract) of the spinal cord and periaqueductal gray matter to modulate transmission of nociceptive stimuli.5,6 Namaka et al7 characterize this as a complex equilibrium of pain-signaling and pain-relieving pathways connecting peripheral and central nervous systems. 
Efficient, rapid transmission of acute responses to a painful stimulus is a self-protection process. In general, acute pain provides an “alarm” that leads to subsequent protective responses; neuropathic pain, however, signals no imminent danger. The operative difference is that neuropathic pain represents a delayed, ongoing response to damage that is no longer acute but which continues to be expressed as painful sensations. 
Sensory neurons damaged by injury, disease, or drugs produce spontaneous discharges leading to sustained levels of excitability. These ectopic discharges begin to “cross talk” with adjacent uninjured nerve fibers, resulting in amplification of pain impulses (peripheral sensitization). This hyperexcitability leads to greater transmitter release causing increased response by spinal cord neurons (central sensitization). This process, known as “windup,” accounts for the fact that the level of perceived pain is far greater than what is expected based on what can be observed.8,9 
Painful nerve stimulation leads to activation of N-methyl-d-aspartate (NMDA) receptors on postsynaptic membranes in the dorsal horn of the spinal cord. 6(pp207-228) Release of NMDA, a modulating neurotransmitter, is coupled with subsequent release of glutamate, an excitatory neurotransmitter. The resultant extended depolarization (influx of calcium and sodium and efflux of potassium) produces much larger than usual postsynaptic potentials, known as synaptic potentiation. Spinal windup has been described as “continuous increased excitability of central neuronal membranes with persistent potentiation.”9,10 Neurons of peripheral and central nervous systems continue to transmit pain signals beyond an original injury, thus activating an ongoing, continuous central pain response (Figure 1). Devor et al11 presented evidence showing that damaged sensory fibers have a higher concentration of sodium channels, an alteration that would increase spontaneous firing. 
Characterization of Neuropathic Pain
Symptoms described by patients with neuropathic pain are myriad (see Sidebar on page ES45), representing a variety of possible nerve injuries implicated in causation.2 Neuropathic pain sufferers complain of numbness, burning, or tingling, or a combination; they describe electric shock–like, prickly, or pins and needles sensations. Patients completing the McGill Pain Questionnaire 12 described their pain using terms such as “punishing-cruel” and “tiring-exhausting.” In 1990, Boureau et al13 identified six adjectives used substantially more frequently to describe neuropathic pain; electric shock, burning, and tingling were most commonly used (53%, 54%, and 48%, respectively), in addition to cold, pricking, and itching. These terms should suggest a neuropathic etiology for pain. 
Figure 1.
Complex neuropathic pain. (NMDA indicates N-methyl-d-aspartate.)
Figure 1.
Complex neuropathic pain. (NMDA indicates N-methyl-d-aspartate.)
Several types of abnormal sensations, or dysesthesias, may occur alone or in addition to other specific complaints in patients with neuropathic pain (Table 2). Unlike usual responses to such discomfort, these irritating or painful sensations occur in the absence of an apparent cause. A common example is the severe, aching, “toothache-like” response elicited by a cool draft of air on the cheek of a patient suffering from trigeminal neuralgia. 
Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain

Symptom or Sign

Description
▪ Allodynia Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus)
▪ Anesthesia Loss of normal sensation to the affected region
▪ Dysesthesia Spontaneous or evoked unpleasant abnormal sensations
▪ Hyperalgesia Exaggerated response to a mildly noxious stimulus applied to the affected region
▪ Hyperpathia Delayed and explosive response to a noxious stimulus applied to the affected region
▪ Hypoesthesia Reduction of normal sensation to the affected region
▪ Paresthesias Nonpainful spontaneous abnormal sensations
▪ Phantom Pain Pain from a specific site that no longer exists (eg, amputated limb) or where there is no current injury
▪ Referred Pain
Occurs in a region remote from the source
Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain

Symptom or Sign

Description
▪ Allodynia Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus)
▪ Anesthesia Loss of normal sensation to the affected region
▪ Dysesthesia Spontaneous or evoked unpleasant abnormal sensations
▪ Hyperalgesia Exaggerated response to a mildly noxious stimulus applied to the affected region
▪ Hyperpathia Delayed and explosive response to a noxious stimulus applied to the affected region
▪ Hypoesthesia Reduction of normal sensation to the affected region
▪ Paresthesias Nonpainful spontaneous abnormal sensations
▪ Phantom Pain Pain from a specific site that no longer exists (eg, amputated limb) or where there is no current injury
▪ Referred Pain
Occurs in a region remote from the source
×
Allodynia is a painful response to an otherwise benign stimulus. Taken to the extreme (eg, inability to remove the stimulus), this response can result in an agonizing neuropathic symptom known as hyperpathia. Another example of this condition is “touch sensitivity” of badly sunburned skin, where even light stroking of an inflamed area causes extreme discomfort; like neuropathic pain, this response seems out of proportion to the injury. 
Pharmacologic induction of local anesthesia or hypoesthesia by lidocaine or transdermal fentanyl produces a predictable duration of action; this is not the case with neuropathic-induced anesthesia or hypoesthesia. The discomfort of one's foot “falling asleep” is a common paresthesia. That uncomfortable sensation is self-limiting and resolves spontaneously, unlike the continuous, self-perpetuating, and annoying sensation of pins and needles caused by neuropathic pain. 
Pain Scales for Assessing Neuropathic Pain
Following adoption of pain as “the fifth vital sign” by the Joint Commission on Accreditation of Healthcare Organizations, clinicians have been exposed to varied analog assessment forms such as the Wong Baker faces scale for rating pain intensity. Recently, pain researchers have focused attention on a theory that accurate measurement of pain quality could provide insight into treatment effects too subtle to be noticed when global measures are similar.14 This accuracy is especially important for neuropathic pain, because specific sensory characteristics (eg, burning, tingling) may spotlight pathophysiologic mechanisms of such pain and give clues to those types of intervention most likely to result in palliation. 
Examples of standardized scales used for pain assessment include: 
  • Short Form McGill Pain Questionnaire (SF-MPQ)12
  • 100-mm visual analog scale (VAS)15
  • numeric rating16 and faces scales17
  • Pain Disability Index18
  • Pain Catastrophizing Scale (PCS)19and
  • Neuropathic Pain Scale (NPS).20.
One of the most widely used current evaluations is the 0-10 rating where “0” means “I have no pain” and “10” is “the worst pain I ever had.” Investigators for the Shingles Prevention Trial devised a specific pain assessment tool for calculating a herpes zoster severity-of-illness score, the Zoster Brief Pain Inventory in which patients are asked questions to rate their pain and also are able to shade areas on a diagram to indicate the parts of their bodies that were most affected.21 
These scales underscore the fact that it may be difficult for clinicians to assess or rate a patient's pain because the level of perceived discomfort may be much greater than what is observable. Pain scales provide useful, standardized, and validated tools for charting an individual's response to a pain-control intervention. In addition, detailed documentation utilizing accepted pain scales to assess a patient's level of discomfort provides protection from legal challenges regarding any prescribed pharmacotherapy. 
Treatment of Patients With Neuropathic Pain
Neuropathic pain tends to exhibit a relatively poor response to traditional analgesics.5,7 No cure for neuropathy exists; however, prevention of progression as in potentially reversible cases of hyperglycemic neuropathy22 or alcohol-induced neuropathy, palliation of pain, restoration of therapeutic sleep, maintenance of function, and improvement in overall quality of life remain the mainstays of treatment. 
Figure 2.
Treatment options for patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 2.
Treatment options for patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Adequate treatment trials demand a long-term commitment from both patient and physician.4 For any regimen to be effective, both adherence to prescribed agents and an adequate time for the trial are needed. As with many difficult medical problems, a multidisciplinary approach to treatment is often the most successful. A multidisciplinary pain relief team includes primary care physicians, neurologists, pain specialists such as anesthesiologists or neurosurgeons, psychiatrists, psychologists, pastoral counselors, advanced practice nurses, clinical pharmacologists, and others. As always, the most important member of this team is the patient. 
Medications used to treat neuropathic pain include over-the-counter analgesics, anticonvulsants, tricyclic antidepressants (TCAs), and selective serotonin-norepinephrine reuptake inhibitors (SSNRIs), topical anesthetic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), antiarrhythmics, non-narcotic analgesics, and opioids2,4,7 (Figure 2). This varied armamentarium reflects heterogeneity in this patient group and the different pathophysiologic mechanisms postulated to produce neuropathic pain. Seven agents (Figure 3) should be avoided (never used) in the treatment of patients with DPN. 
Examples of heterogeneity in presentation of neuropathic pain is reflected in DPN or PHN versus deafferentation (central) pain due to multiple sclerosis or spinal cord injury. Patients with DPN tend to complain of burning, tingling pain in their distal extremities, especially foot and ankle pain, and of abdominal paresthesias, perhaps related to gastroparesis.9,23,24 Patients with multiple sclerosis have classic electric shocklike neuropathic pain (eg, Lhermitte's sign), characteristic of demyelinating disease. Patients with multiple sclerosis have diffuse paresthesias, hypoesthesia, and other symptoms. Patients having spinal cord injury with incomplete myelopathy manifest pain akin to phantom limb pain: unpleasant sensations in body regions below the level of cord injury. Inspection of the painful site yields no evidence of inflammation or obvious injury. In fact, the injury occurred at the time of insult to the spinal cord. These pains may mystify physicians and can cause significant distress to patients. (See “Patient Perspectives on Pain” Sidebar on page ES45.) 
Figure 3.
Agents that should not be used in the treatment of patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 3.
Agents that should not be used in the treatment of patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Recently, Hansson and Dickenson25 noted that treatment of patients with neuropathy may be based on “shared commonalities despite multiple etiologies.” They concluded their review by stating that because there is little information on drugs affecting specific pain symptoms and no clear rationale for their use, treatment trials are warranted.25 This conclusion supports use of empiricism in selection of a treatment regimen for neuropathic pain. 
Numerous treatment algorithms list trials of common analgesics such as ibuprofen or acetaminophen, topical treatment such as capsaicin cream or lidocaine patches, TCAs or other antidepressants (eg, amitriptyline hydrochloride, desipramine hydrochloride), and anticonvulsants (eg, carbamazepine, gabapentin, pregabalin, lamotrigine) as first-line therapy for neuropathic pain.5,7,9 These medications may be used alone or in combination. An example of clinical use of combination therapies is the pratice of initiating a neuroactive agent such as gabapentin concomitant with opioid analgesic (eg, oxycodone hydrochloride) for treatment of patient with postherpetic neuralgia. The choice of pharmacotherapy should be directed toward the type of painful symptom described. 
Commonalities in presentation may influence the clinician's choice of pain medication. For example, PHN and DPN may produce spasms, burning, and tingling characteristic of neuronal hyperexcitability. Nervous system excitability can produce seizure activity. Thus, anticonvulsants are used with reasonable efficacy to treat patients with neuropathic pain.7,8 
Anticonvulsants
Neuropathic pain sufferers may respond to gabapentin, which is structurally related to γ-aminobutyric acid (GABA), a pain-modulating neurotransmitter. Gabapentin readily crosses the blood-brain barrier and has been studied for treatment of patients with DPN; pain relief efficacy was similar to that of TCAs except for a shorter onset of action. In a study of gabapentin as monotherapy, Backonja et al23 noted that relatively high doses were needed (3600 mg/d was the forced maximum dose, ie, the target maximum dose). Higher doses, however, limited upward titration because of adverse effects, most common being dizziness and somnolence; weight gain, nausea, abdominal pain, asthenia, and other symptoms were also reported. 
Pregabalin is a member of the gabapentinoid family that binds to α-2-δ subunit of the voltage-gated calcium channel with a higher binding affinity than gabapentin.26 Several studies have shown favorable effects in patients with painful diabetic neuropathy, and dose titration may be easier for pregabalin. The European Federation of Neurological Societies (EFNS) Task Force guidelines on pharmacologic treatment of patients with neuropathic pain note that titration with gabapentin should be slow and individualized with initial dosages of 300 mg/d (less in geriatric patients); pregabalin titration can occur more rapidly and has a shorter onset of action (<1 week).27 Additionally, pregabalin may be dosed twice a day, whereas gabapentin must be taken three times daily. 
Recently, pregabalin received US Food and Drug Administration (FDA) approval for treatment of patients with pain due to fibromyalgia, which is considered to be another centrally mediated pain syndrome. In a 14-week, randomized double-blind placebo-controlled trial, patients received pregabalin twice daily in doses ranging from 300 mg to 600 mg.28 Clinically significant reductions in pain scores were noted as early as week one, and efficacy was also shown for improvement in global assessment, functional status and sleep, compared with placebo.28 
Other anticonvulsants have been used for both PHN and DPN; eg, patients with trigeminal neuralgia have been treated for decades with carbamazepine, a sodium-channel blocker. Oxcarbazepine, a successor to carbamazepine, has shown limited efficacy in clinical trials and will not be marketed in the United States, though the EFNS guidelines support its use at initially low doses with slow upward titration and careful monitoring for hyponatremia.22,27 
A study of divalproex sodium for PHN noted subjective improvement in the treatment group compared with the group receiving placebo and found clinically significant adverse effects in only one patient.29 Trials of other anticonvulants (eg, lamotrigine) may be indicated in patients with neuropathic pain refractory to alternatives. To minimize the occurrence of rash (a major adverse effect), lamotrigine must be titrated very slowly and should not be used in combination with valproate.27 
Topical Anesthetic Agents
Patients with PHN or other localized regions of peripheral neuropathy may respond well to topical 5% lidocaine patches, especially if the region of pain is relatively small and circumscribed. Studies have demonstrated efficacy of topical lidocaine either as monotherapy or in combination with oral agents used to treat patients with neuropathic pain; it was safe, easily administered, and had minimal side effects.30,31 Capsaicin cream has also been used effectively in patients with PHN but must be carefully applied because of its powerful irritating effects (which are related to the degree of subsequent analgesia). 
Antidepressants
Tricyclic antidepressants have been used for treatment of patients with DPN since the 1970s. These agents have documented pain-control efficacy32 but are limited by a slow onset of action (analgesia in days to weeks), anticholinergic side effects (eg, dry mouth, blurred vision, confusion/sedation, and urinary retention), and potential cardiac toxicity. Amitriptyline hydrochloride is the most extensively studied at oral doses of 10 mg to 25 mg at bedtime. This dose can be slowly titrated with escalating amounts every 4 to 7 days. Frail and elderly patients may be unable to tolerate therapeutic doses of amitriptyline because of sedation. Desipramine hydrochloride and nortriptyline are less-sedating alternatives to amitriptyline; plasma drug levels are available for the latter. 
The advent of selective serotonin reuptake inhibitors (SSRIs) gave hope that they could be used for chronic pain without the concerns of cardiotoxicity and anticholinergic adverse effects. However, pain control results have been disappointing; they may be useful adjuncts to treat patients who have pain with depression when TCAs are contraindicated. Duloxetine hydrochloride and venlafaxine hydrochloride are SSNRIs that have received FDA approval for the PHN indication. 
Figure 4.
Osteopathic primary and adjunctive treatment options for patients with neuropathic pain.
Figure 4.
Osteopathic primary and adjunctive treatment options for patients with neuropathic pain.
Patients with neuropathic pain are prone to depression, drug dependency, and insomnia. Interrupted sleep is one of the most difficult problems facing patients with neuropathy, as there is no way to escape the discomforting symptom. Antidepressants and sedative-hypnotic medications may be prescribed as important adjunctive therapy for neuropathy. 
Antiarrythmics
Neuronal hyperexcitability resulting from nerve damage may respond to therapy with antiarrythmic medications. A randomized trial of amitriptyline and mexiletine in a group of patients with painful distal sensory neuropathy due to HIV infection showed that dosages of amitriptyline hydrochloride up to 100 mg/d and mexiletine hydrochloride up to 60 mg/d were generally well tolerated.33 However, there was no evidence of significant pain relief for this indication. 
Anti-Inflammatory Agents
The usefulness of NSAIDs such as aspirin and ibuprofen for neuropathic pain is limited. Use of NSAIDs for DPN should be discouraged because of the adverse effects of these drugs on renal function. Selective cyclooxygenase-2 (COX-2) inhibitors have been under scrutiny for adverse cardiovascular events, and rofecoxib has lost FDA approval. Celecoxib, the remaining agent, cannot be recommended for the long-term administration needed to treat patients with neuropathic pain syndromes. 
Opioid Analgesics
In response to severe or persistent pain, interneurons in the dorsal horn release endogenous opioids that reduce perceived pain. These endogenous substances (enkephalins, endorphins, and dynorphins) play a major role in mechanisms of pain reduction and modulation by preventing transmission of pain signals to higher centers. Exogenously administered opioids mimic physiologic effects of enkephalin and dynorphin at μ-type opioid receptors, which occur throughout the brain and spinal cord.6(pp207-228) This mechanism accounts for opioid efficacy in neuropathic pain syndromes. 
Tramadol, a semisynthetic opioid analgesic, may also affect neuropathic pain by low-affinity binding to μ receptors as well as weak inhibition of norepinephrine and serotonin reuptake, mirroring mechanism of actions of both opioids (former action) and TCAs (latter effect). One trial suggests that tramadol may be better tolerated than TCAs in some individuals with DPN or other neuropathic pain syndromes.34 
Because of concerns about tolerance, abuse, and addiction, prescribing opioids for nonmalignant pain was formerly considered controversial. In recent years, however, much research has supported use of these agents. Opioids are now commonly and effectively prescribed to treat patients for neuropathic pain.7,24,32,35,36 
A double-blind, dose-response study reported in 2003 used levorphanol tartrate (3 mg equivalent to 45 mg to 90 mg of oral morphine sulfate or 30 mg to 45 mg of oral oxycodone hydrochloride) and showed a 48% overall reduction in pain and moderate or better pain relief in 66% of patients.35 These researchers noted that higher doses are more effective in reducing the intensity of chronic neuropathic pain. They also demonstrated that tolerance was not a clinically significant problem as only 4 (9%) of the 43 patients in the high-strength group ever reached the maximal allowed dose. Further, they noted no addictive behavior.35 
Raja et al32 studied pain intensity, pain relief, cognitive and physical functioning, sleep, mood, side effects, and treatment preference in a group of patients with PHN. They compared responses to TCA therapy with those to opioids, noting that both agents act via independent mechanisms and varied individual effects. This investigation observed that patients who completed all three treatments (including placebo) preferred opioids to TCAs; it was concluded that opioids effectively treat patients with PHN without impairment of cognition.32 
NMDA-Receptor Antagonists
Nerve injury results in upregulation of NMDA receptors through repeated firing of peripheral afferent fibers and release of glutamate. This results in greater-than-expected peripheral pain.6(pp207-228) NMDA-receptor blockers have been studied for their efficacy in chronic pain. Currently available agents include dextromethorphan hydrobromide, memantine hydrochloride, and ketamine.10,37 
NMDA receptors have been studied for their role in opioid tolerance. Adjuvant use of ketamine may reduce morphine requirements and cause improvement in analgesia, as noted in case reports by Bell.38 A larger study showed that ketamine improves morphine analgesia in difficult pain syndromes (neuropathic pain caused by cancer); however, adverse CNS effects such as psychomimetic effects were noted.39 The authors state that future studies must address treatments to prevent or reduce these adverse central effects of ketamine. 

Patient Perspectives on Pain

In preparing to write this overview of neuropathic pain, the author initiated conversations with several of her patients to elicit descriptions of how their individual pain symptoms feel and how it has affected their lives. Their responses follow.

From a 34-year-old man with T10 paraplegia:

“You know, you'd have to have a complete injury not to feel pain. Not all quads and paras have complete injuries; we do have pain. The worst pain kind of starts like a pressure, like from an overworked muscle. Then it progresses into a burning, like a heat you can't make stop. It gets to the point where—honestly, doc—you don't want to live anymore.

“You know, you get a few days of bad weather and the pain starts up, and you're stuck in bed 3 or 4 days, it's rough.

“I haven't had a full night's sleep since 1997. [Motor vehicle accident in 1997 caused spinal cord injury.]

“Don't forget to tell your readers that chronic pain destroys relationships. It can destroy friendships and social life. Friends call to ask me to go down the shore and sit on the beach; I can't do that! Fifteen minutes in the car and I have to turn around and go back so I can lie down.” [Patient has symptoms of autonomic dysfunction, such as sweating and tachycardia, that are the cause.]

From a 53-year-old man with type 1 diabetes mellitus:

“The pain in my hands is so bad sometimes, it feels like my hands are stuffed too tightly into the skin and they are going to explode. It keeps me awake at night. And my feet don't feel like feet. Half the time they are numb blocks, and the other half they're burning.

“My family is going to Europe this summer, and I decided to stay home. I just can't sit that long on a plane without being in extreme pain.

“I guess you can tell that my mood is affected by this.” [Nonetheless, this patient refuses antidepressant therapy on the grounds that he already takes too many medications.]

From a 56-year-old woman with chronic progressive multiple sclerosis:

“I know you doctors try to help us, but you can't know how it feels. When I try to move sometimes, it's like someone is jabbing me with a hot poker. My muscles jump, and it feels like the nerves are being shocked. You know, this is just miserable.

“I hate to let my daughter see me when I'm in pain, because I look and feel like a witch. I think it scares her, and that's why she doesn't come to visit me very often. I miss being able to watch her grow up.” [The patient has lived in a nursing facility for more than 10 years; she is wheelchair bound and unable to perform self-care.]

 
Cannabinoids
Administration of cannabinoids for central neuropathic pain is not approved by the FDA. However, several European studies exploring their use in patients with chronic pain indicated efficacy in patients with multiple sclerosis in treatment of spasticity and pain, and have shown decreases in allodynia or hyperalgesia in various animal models. 
A Danish study tested use of synthetic δ-9-tetrahydrocannabinol (dronabinol) and showed a modest but clinically relevant effect on central pain in patients with multiple sclerosis.40 Central, neuropathic pain in patients with multiple sclerosis was also studied using a whole plant cannabis–based medicine containing δ-9-tetrahydrocannabinol and cannabidiol (CBM). This investigation documented reductions in pain using a visual analog scale and increases in quality of life measures such as sleep. Although treatment group subjects reported more side effects than those in the nontreatment group, it was concluded that CBM was effective in reducing pain and sleep disturbance in patients with multiple sclerosis–related central pain.40 
Combined Analgesic Therapy
Clinical experience supports the use of more than one agent for patients with refractory neuropathic pain. Because physiologic mechanisms causing pain can be different, use of more than one type of medication may be necessary. Monotherapy may be desirable for both ease of administration and reduction of potential side effects, but this approach may not achieve satisfactory pain relief. A strategy of using two or more agents with different mechanims of action at lower doses to achieve synergistic pain efficacy is not uncommon. Several studies have evaluated effectiveness of this strategy.32,33,41 
Gilron et al41 used a four-period crossover trial to assess efficacy of morphine and gabapentin alone, these drugs in combination, and active placebo (in the form of low-dose lorazepam). They concluded that gabapentin substantially enhanced morphine efficacy (P=.03), and suggested that further studies of combination drug trials are warranted. 
Osteopathic physicians are trained to treat the whole person, and, with this goal in mind, it must be remembered that side effects of medications may pose limitations to their use. Skillful and judicious use of adjuvants, here defined as any agent that enables the use of a primary medication to its full dose potential, is mandated. An obvious example of this practice is the customary use of laxatives in combination with opioids. 
Other Treatment Modalities
Osteopathic manipulative treatment (OMT) should be offered to all patients with neuropathic or other chronic pain syndromes as primary or adjunctive therapy, or both (Figure 4) Myofascial trigger point release for carpal or tarsal tunnel syndrome pain is an example of an effective primary technique. Indirect or passive myofascial techniques may be used to address all regions of tissue texture change. Adjunctively, educating patients with neuropathic pain about the importance of postural influence and functional movement can enhance their sense of well-being and maintain or improve physical functioning. Prescribing flexion/stretching exercises for neuropathic low back pain assures that patients maintain active range of motion and ambulatory function. (See http://www.spinalinjuryfoundation.org/101_new/williams.htm and http://www.catmanor.com/moonbeam/back/flexion.html.) 
As previously noted, drug treatment of patients with neuropathic pain lacks a standardized rationale and relies on clinical empiricism. Despite best efforts at treatment trials, some patients may continue to suffer. In these cases, referral to pain specialists is essential. Surgical interventions such as motor cortex stimulation,42 transcutaneous electrical nerve stimulation (TENS) units, and other peripheral stimulation43 have been shown to be helpful in patients with pain refractory to pharmacotherapy. 
Prophylaxis
An important cause of neuropathic pain is herpes zoster (“shingles”), a condition caused by varicella-zoster virus reactivation decades after the initial episode of chickenpox. Shingles disproportionately affects the population older than 60 years, the group likely to be contending with numerous other medical concerns. Unfortunately, the discomfort of shingles represents only the beginning of the problem for many patients who suffer for months or years from debilitating PHN.21 
A large prospective, randomized placebo-controlled double-blind study was recently completed by the Shingles Prevention Study Group.21 This investigation included 38,546 adults aged 60 years or older and used a highly potent zoster vaccine (several times the concentration of that used for primary vaccination against chickenpox in children). Vaccine recipients showed reduced burden of illness (incidence and severity) by greater than half (61.1%; P<.001). The incidence of herpes zoster was reduced by 51.3%, and, most significantly, incidence of PHN was reduced by 66.5% (P<.001). These authors suggest that decreases in PHN morbidity more than adequately offset costs of large-scale immunization of individuals aged 60 years or older.21 This vaccine was approved by the FDA in May 2006. 
The Advisory Committee on Immunization Practices44 currently recommends immunization with the zoster vaccine, live for all individuals aged 60 or older who have not had herpes zoster. Contraindications to vaccine administration include history of anaphylactic reaction to any product component, serious current illness (or temperature ≥38.5° C [101.3°F]), immunodeficiency states (eg, lymphoma, leukemia, or malignant neoplasm affecting the bone marrow or lymphatic system), AIDS or other clinical manifestations of HIV, immunosuppressive therapy including high-dose corticosteroids, untreated tuberculosis, or patients who may be pregnant. 
Following is an anecdotal description of a patient who is typically seen in primary care with the chief complaint of pain. 
Case Presentation
Harry, a 57-year-old white man with greater than a 40-year history of type 1 diabetes mellitus, has maintained good diabetic control with long-acting evening insulin and several short-acting insulin injections for coverage with meals during the day. Except for occasional episodes of gastroparesis that result in a sense of mid-chest fullness and occasional nausea (for which he takes metoclopramide, a dopamine antagonist used to improve gastric motility, and pantoprazole, a proton pump inhibitor for erosive gastritis), he generally reports no problems. Recently, however, unrelenting pain has developed in both lower extremities. Harry describes the pain as constant generalized numbness that worsens into a deep burning/tingling sensation, especially at night and upon awakening. Walking for several minutes seems to alleviate the burning and tingling sensation, though the numbness persists; but awakening at night and having to “walk it off” has caused him substantial loss of sleep. Harry has been irritable and distracted at work and with family members. During the past several days, in addition to the numbness, Harry complains that when he dons his socks, his feet have the excruciating sensation that they are “being stung by red ants” for several minutes. 
Patient Approach and Considerations
Which of the following does not describe the type of pain this patient is experiencing? 
  • nociceptive *
  • allodynia
  • neuropathic
  • diabetic sensory polyneuropathy
  • paresthesia
Of the following options, which is the most appropriate initial treatment strategy for the patient at this visit? 
  • referral to an endocrinologist
  • increased “tight control” of blood glucose
  • psychiatric evaluation
  • pregabalin titration *
  • long-acting morphine
The best plan for adjunctive therapy for this patient will include 
  • only OMT
  • only psychological counseling
  • duloxetine or venlafaxine plus OMT
  • diet and exercise prescription plus psychological counseling
  • duloxetine or venlafaxine, OMT, diet and exercise prescription, and psychological counseling *
Discussion
The patient is having neuropathic pain characterized by paresthesia (burning, tingling), anesthesia (numbness) and allodynia (painful response to putting on socks) due to progression of diabetic sensory polyneuropathy resulting from many years of type 1 diabetes mellitus. Intensive diabetes therapy (“tight blood glucose control” as utilized in the Diabetes Control and Complications Trial [DCCT]) in patients with type 1 diabetes mellitus has been shown to have some benefit in forestalling the onset of neuropathy but not in preventing the development of polyneuropathy and autonomic neuropathy.45 Referral for endocrinologic and psychiatric evaluation may be helpful in the long-term, but will not immediately address the complaint of unremitting pain that is affecting Harry's psychosocial function and quality of life. 
Long-acting opioid analgesia may be helpful in patients in whom other modalities have proven unsuccessful. Long-acting agents are best initiated only in patients who have had their dosage requirement carefully titrated using short-acting “immediate release” agents. In such patients, a long-acting/split-dose regimen with short-acting “breakthrough” doses as needed may be beneficial. 
Pregabalin has shown efficacy in controlling diabetic peripheral neuropathic pain, is easily administered in twice-daily doses, and does not require protracted up-titration schedule. Thus, it is a good first choice. An alternative would be an SSNRI (duloxetine or venlafaxine) to address the painful symptoms and possibly improve mood, sleep, and general quality of life. The SSNRI could be initiated as monotherapy, or adjunctive to other pain medication that Harry is using. 
Osteopathic physicians are trained and motivated to treat the whole patient. The holistic approach to Harry would include referrals to other appropriate disciplines such as psychology or physical therapy, pain specialists, and endocrinologists as indicated. Osteopathic manipulative treatment, especially myofascial release technique, remains a mainstay as valuable adjunctive treatment to improve Harry's range of motion, muscle relaxation, ambulation, and sense of well-being. 
Comment
Relief from chronic pain has the potential to improve all aspects of a patient's life. Social and physical functioning, relationships, mood, sleep, overall health, and well-being are positively impacted by adequate control of debilitating pain symptoms. Osteopathic physicians are committed to treating the whole person and have a unique ability to diagnose and treat with their hands as well as with medications. The concept of working with other professionals and the patient to achieve pain control is congruent with principles of osteopathic practice. It is specifically this type of treatment model that has the best chance for success in treating patients with neuropathic pain. 
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Figure 1.
Complex neuropathic pain. (NMDA indicates N-methyl-d-aspartate.)
Figure 1.
Complex neuropathic pain. (NMDA indicates N-methyl-d-aspartate.)
Figure 2.
Treatment options for patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 2.
Treatment options for patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 3.
Agents that should not be used in the treatment of patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 3.
Agents that should not be used in the treatment of patients with diabetic peripheral neuropathic pain. (Source: Argoff CE, Backonia M-M, Belgrade, MJ, Bennett GJ, Clark MR, Cole BE, et al. Consensus guidelines: treatment planning options. Mayo Clin Proc. 2006;81[4 suppl]:S12-S25.)
Figure 4.
Osteopathic primary and adjunctive treatment options for patients with neuropathic pain.
Figure 4.
Osteopathic primary and adjunctive treatment options for patients with neuropathic pain.
Table 1
Estimated Prevalence of Neuropathic Pain in the United States

Condition

No. per 100,000
□ Diabetic peripheral neuropathy600
□ Postherpetic neuralgia 500
□ Cancer-associated200
□ Spinal cord injury 120
□ Causalgia and reflex sympathetic dystrophy100
□ Multiple sclerosis 50
□ Phantom pain50
□ Poststroke pain 30
□ HIV-associated15
□ Trigeminal neuralgia (tic douloureux) 15
□ Low back pain—associated2,100
Total (excluding back pain) 1,680 M
Total (including back pain)3,780 M
 * Based on population of 270 million.
 Source: Bennett GJ. Neuropathic pain: new insights, new interventions.Hosp Pract (Off Ed). October 15, 1998;33(10):95-98, 101-104, 107-110 passim.
Table 1
Estimated Prevalence of Neuropathic Pain in the United States

Condition

No. per 100,000
□ Diabetic peripheral neuropathy600
□ Postherpetic neuralgia 500
□ Cancer-associated200
□ Spinal cord injury 120
□ Causalgia and reflex sympathetic dystrophy100
□ Multiple sclerosis 50
□ Phantom pain50
□ Poststroke pain 30
□ HIV-associated15
□ Trigeminal neuralgia (tic douloureux) 15
□ Low back pain—associated2,100
Total (excluding back pain) 1,680 M
Total (including back pain)3,780 M
 * Based on population of 270 million.
 Source: Bennett GJ. Neuropathic pain: new insights, new interventions.Hosp Pract (Off Ed). October 15, 1998;33(10):95-98, 101-104, 107-110 passim.
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Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain

Symptom or Sign

Description
▪ Allodynia Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus)
▪ Anesthesia Loss of normal sensation to the affected region
▪ Dysesthesia Spontaneous or evoked unpleasant abnormal sensations
▪ Hyperalgesia Exaggerated response to a mildly noxious stimulus applied to the affected region
▪ Hyperpathia Delayed and explosive response to a noxious stimulus applied to the affected region
▪ Hypoesthesia Reduction of normal sensation to the affected region
▪ Paresthesias Nonpainful spontaneous abnormal sensations
▪ Phantom Pain Pain from a specific site that no longer exists (eg, amputated limb) or where there is no current injury
▪ Referred Pain
Occurs in a region remote from the source
Table 2
Sensory Symptoms and Signs Associated With Neuropathic Pain

Symptom or Sign

Description
▪ Allodynia Pain due to nonnoxious stimuli (clothing, light touch) when applied to the affected area. May be mechanical (eg, caused by light pressure), dynamic (caused by nonpainful movement of a stimulus), or thermal (caused by nonpainful warm, or cool stimulus)
▪ Anesthesia Loss of normal sensation to the affected region
▪ Dysesthesia Spontaneous or evoked unpleasant abnormal sensations
▪ Hyperalgesia Exaggerated response to a mildly noxious stimulus applied to the affected region
▪ Hyperpathia Delayed and explosive response to a noxious stimulus applied to the affected region
▪ Hypoesthesia Reduction of normal sensation to the affected region
▪ Paresthesias Nonpainful spontaneous abnormal sensations
▪ Phantom Pain Pain from a specific site that no longer exists (eg, amputated limb) or where there is no current injury
▪ Referred Pain
Occurs in a region remote from the source
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