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As if to accentuate the difference between inflammatory and neuropathic pain, it is prudent to discuss the management of neuropathic pain compared to the treatment of inflammatory pain. In the latter, treatment usually coincides with the pain's eventual elimination and the return of the patient to his/her pre-pain, productive lifestyle. Psychosocial consequences of the pain usually have a limited impact, which facilitates the thoroughness of the specified treatment. Given the reality of CNS neuroadaptation and functional reorganization associated with neuropathic pain, it is appropriate to refer to managing the pain much in the same way as medical treatment is provided for other intractable diseases such as diabetes and asthma. As such, the logical goals of management for neuropathic pain over time are to (1) achieve maximum reduction in pain by decreasing the frequency and/or the intensity of the pain, (2) maintain in the patient's treatment program only those modalities that are clearly providing a positive effect on the symptoms, (3) increase the patient's functional capacity (the ability to function at as high a level as possible whether at home, as a volunteer, or at productive employment), (4) provide the patient with assistance for coping with residual pain and the negative psychosocial aspects of pain, and (5) respond on behalf of the patient in administrative and legal issues (i.e., workman's compensation forms, disability matters, lawsuits).
It is essential that the patient be actively involved in the treatment planning process.[16] [30] One must fully understand the patient's agenda in this regard to comprehend some of the choices that patients make. This involvement is predicated on the patient's having a fundamental understanding of what is wrong and why the treatment options being discussed are appropriate. Von Korff showed that patients with low back pain who were involved by education in their care decisions achieved equivalent therapeutic results, but with less medication, less bed rest, and lower costs when compared to a group of similar patients receiving more traditional, conservative therapy.[39]
The patient's systematic workup fuels the informative discussion, as the presence of pathology related to the pain complaints has been established to the extent possible. Insight into the fact that the nervous system has been changed by the persistence and severity of the patient's pain is often a comforting and mind-opening concept, because it validates that the patient has a problem, offers an explanation as to why the pain continues despite all the doctor's visits and negative tests, and helps the patient understand why treatment must continue long beyond the time when all evidence of the original problem has disappeared.
In an ideal world, although the workup of the patient reflects multidisciplinary input and although patients may have similar diagnoses, the treatment should be individualized in application. In reality, when a team approach to patient care is present, a decision must be made as to who on that team will actually manage the patient. Often the patient with neuropathic pain will have had single therapeutic options tried at various times. The minimal reduction in pain gained as a result is trivial to the patient. If a number of "somewhat beneficial" treatments are applied at the same time in a coordinated program, the benefits are likely to be greater. All pain cannot be managed in the same way in all patients, since their needs differ. As a matter of fact, just taking the physical pain away, as with nerve blocks, will not immediately reset all of the adverse consequences of "the pain" in the patient's life (e.g., alienation of family members, being out of work for months at a time, decreased self-esteem, the sense of lost entitlement).[8] [27] [28]
Because medications are so prevalent, and because medication prescriptions are so easy for the health care professional to write and therefore expected by the patient, medications are the most common management technique for neuropathic pain. As with any treatment, they can induce annoying side effects, if not life-threatening complications. Therefore, even with the simplest of therapies, the choices made must be carefully guided by the identified mechanism(s) for the pain, while also respecting the patient's current medical and physical condition.[40]
Probably the most commonly prescribed analgesics are nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen.[40] [41] [42] The former block cyclooxygenase (COX), the enzyme that initiates the breakdown of arachidonic acid into various prostaglandins, thromboxane, and leukotrienes, all of which are inflammatory mediators. The subsequent potent anti-inflammatory effects of NSAIDs can decrease musculoskeletal, mild to moderate inflammatory, and bony pain (due to the induction of prostaglandins at the site of metastatic disease).
Newer on the scene are the specific COX-II inhibitors.[43] These drugs block only the COX-II enzyme, ordinarily active in the face of injury and associated with prominent pain and inflammation. The clinical use of these drugs has a more focused effect on inflammatory-related pain, a markedly reduced profile of side effects compared to the more traditional NSAIDs, and comparable analgesic efficacy.[43] Data indicate that the antiprostaglandin effects of NSAIDs in pain management may be more profound in the spinal cord than at peripheral sites, although this has been noted only in inflammatory pain.[44]
When traditional NSAIDs are poorly tolerated or contraindicated, acetaminophen is an acceptable alternative.[41] [42] [45] It is often combined with other known opioid analgesics to enhance the pain-relieving effect. It is important to acknowledge this compounding of drugs, because efforts to increase analgesia with such preparations can put the patient at risk for acetaminophen toxicity. Acetaminophen has a central, but not a peripheral, anti-prostaglandin effect. It decreases fever and blocks hyperalgesia induced by NMDA receptor activation and substance P in the spinal cord.[45]
When pain intensity surpasses that which responds to these drugs, consideration may be given to the use of tramadol.[41] [46] This synthetic drug has a mild opioid analgesic effect, given its action at mu-receptors. More significant in patients with neuropathic pain is the additional effect of tramadol to block the reuptake of serotonin and norepinephrine. These common substances have analgesic effects, especially within the descending pain modulation system from the brain to the spinal cord. Tramadol may be useful in patients taking low-dose hydrocodone or oxycodone, since it can replace the latter.
Theoretically, tramadol should be especially effective in patients with neuropathic pain because of its dual mechanism. Boureau and colleagues studied the use of tramadol for 6 weeks in 127 patients with post-herpetic neuralgia.[46] The patients using tramadol had more pain relief and tolerated the drug well. Tramadol should be used cautiously in patients taking tricyclic antidepressants because both drugs lower the seizure threshold, and the occasional patient has developed a drug-related seizure.
The use of opioid medications for pain management is a time-honored
practice ( Table 73-1
). Their
use in patients with inflammatory pain can lead swiftly to a marked reduction in
clinical pain. Concerns about psychological dependence, drug abuse, and addiction
are generally irrelevant in this setting given the short length of treatment necessary
to correct the painful condition.[42]
[47]
[48]
Even physiologic tolerance (decreasing analgesic
effect from a previously effective dose) is generally not an issue. However, when
patients manifest the attitude, behavior, and psychosocial ramifications of their
intractable
|
|
Dose | |
|---|---|---|
| Drug * | Oral (mg) | IM (mg) |
| Methadone (Dolophine) | 10.0 | 8.8 |
| Alphaprodine (Nisentil) | — | 45.0 |
| Butorphanol (Stadol) | — | 2.0 |
| Codeine | 200.0 | 130.0 |
| Diacetylmorphine (heroin) | — | 3.0 |
| Fentanyl | — | 0.1 |
| Hydromorphone HCl (Dilaudid) | 7.5 | 1.5 |
| Meperidine (Demerol) | 200.0 | 50.0 |
| Morphine | 60.0 | 10.0 |
| Oxycodone (Percodan) | 30.0 | 15.0 |
| Oxymorphone (Numorphan) | — | 1.5 |
| Pentazocine (Talwin) | 180.0 | 60.0 |
| Propoxyphene HCl (Darvon) | 260.0 | — |
| Propoxyphene napsylate (Darvon-N) | 400.0 | — |
| IM, intramuscular. | ||
If one adopts this contemporary approach for managing neuropathic pain, it is unlikely that the primary problem is an opioid deficiency. Thus, patients using opioids clinically often offer qualifying reports such as the medications "take the edge off the pain" or "make it more bearable." This lends credence to the concept of using opioids as but one piece of a comprehensive pain management program, because their potential benefit is limited. A significant number of selected patients for this management therapy achieved a stable dosing regimen and did not routinely escalate their opioid use (without there being a major change in the pathophysiology of the primary disease).[42] [47] [48] [49] [50]
In the setting of the chronic use of opioids, concerns about psychological dependence, drug abuse, drug diversion, and addiction, as well as regulatory agency intervention, are valid. These concerns probably restrict the access of potentially useful treatment for a vast number of patients, because all patients with such needs cannot have their drugs supplied or be managed by the current number of pain medicine specialists in this country. Guidelines for the clinical use of opioids in patients with chronic, non-cancer pain (assessment, documentation, treatment, follow-up) have benefit in these circumstances (see Appendix at the end of this chapter for the document used in the author's state of residence). When patients can be screened by a psychologist for assessment of their attitudes and expectations of the use of opioids for pain management and when an opioid agreement clearly defines the risks, benefits, and responsibilities of both the patient and the prescribing doctor, a workable system can usually be established.[48] [51] What becomes most important at patient follow-up after opioids are being used is the patient's ability to function. In contrast to patients
Stable dosing with opioids is not usually associated with impairment of cognitive function.[52] This broaches the relevant question, "Can patients on chronic opioids return to work?" Beyond this issue, it is now recognized that the chronic use of opioids has health-related consequences. Gonadal atrophy and muscle rigidity have been reported.[42] Perhaps more important is the finding that ultimately opioids induce a state of hyperalgesia.[53] Thus, the very treatment deemed essential to manage the intense pain becomes an instigator of pain rather than an ally. Although there are tables listing the equipotent doses of opioids (see Table 73-1 ), extraordinary variation exists among patients in their individual response to this therapeutic modality.
Table 73-2
highlights the significant differences between patients using opioids for pain relief
versus individuals more interested in the drug-related side effects. Initially,
the data did not support the premise that the liberalization of opioid use contributed
to an increase in health consequences related to opioid analgesic abuse.[54]
Subsequently, there has been much-touted trouble with the misuse of some sustained
release opioid preparations, obscuring the genuine benefit of the drugs and the
| Patients | Addicts |
|---|---|
| Control of medications | Medication use not controlled |
| Medications increase quality of life | Medications decrease quality of life |
| Medications are decreased if side effects occur | Medications are continued in the face of side effects |
| Concerned about medical problem | Lack of concern about medical problems |
| Follow the contract | Ignore the contract |
| Medications left over | Never have medication left; often have stories about drug losses and shortages |
| Adapted from Schnoll DS, Finch JJ: Medical education for pain and addiction: Making progress toward answering a need. J Law Med Ethics 22:252–256, 1994. | |
The practical conundrum of a practice prescribing opioids consists of (1) knowing exactly which patients are best suited to receive such therapy and how much drug to give the patient; (2) guaranteeing a consistent supply of the medication; (3) dealing with the innumerable phone calls from certain patients about the side effects of the medication or their nearly constant need for "more medication"; (4) maintaining morale as staff members deal frequently with these demanding patients (who manifest the reality that the opioids do not treat the pain but only cover it up so it is less intense); (5) adhering to the opioid agreement, including random urine screening; and (6) having the honesty to detoxify patients for misbehavior (and distinguishing between an accidental and an intentional misuse of the drug).
Patients with cancer-related pain will manifest features of neuropathic pain. The World Health Organization (WHO) among other authorities states that 70% to 90% of cancer patients should be able to achieve comfort through the intelligent use of current medications.[55] [56] In 1990, the WHO proposed an analgesic ladder, matching the potency of medications to the intensity (but not the mechanism) of a patient's growing pain. Using this algorithm, one starts with non-opioid analgesics, augmented by analgesic adjuncts when pain transitions from mild to moderate intensity. Opioids are added for moderate to severe pain, given by scheduled dosing and with liberal breakthrough medications provided. Morphine is still the gold standard as the variety of formulations in which it is available permits flexibility in choosing the most appropriate route of administration.
The advent of controlled release formulations of opioids has added versatility to the available choices. MS Contin (morphine sulfate) was the first such preparation. Controlled release oxycodone has been shown to be effective for neuropathic pain management as well.[49] Methadone (see Table 73-1 ) has enjoyed an expanded role in the management of neuropathic pain. It has the advantages of being inexpensive, long-lasting (6 to 8 hours expected duration), well absorbed after oral administration, and of exhibiting a low side effect profile.[57] It can be difficult to titrate this drug in certain patients. Methadone now has recognized NMDA-receptor blocking effects which enhance its utility in patients with neuropathic pain. As the necessary doses of opioids escalate in patients with advancing cancer disease, sedation may become a troublesome side effect. This is often reversed by the use of a small dose of dextroamphetamine or methylphenidate, given in the early part of the day.[58] The catecholamine stimulation of these drugs may enhance the perceived analgesic effect of the opioid as well as reverse the annoying sedation.
Transdermal drug delivery systems have evolved such that drugs can reliably penetrate the barrier of the skin.[59] The administration of fentanyl via this technique is a useful tool in managing neuropathic pain and cancer pain, and especially in those in whom nausea with active
The most recent medication available transdermally is lidocaine. [61] It has an advantage over oral medications because there is no related blood level of the drug, side effects are decreased, titration is not necessary, and it is recommended for once-a-day use.
An even broader application of transdermal techniques is shown in the explosive growth of the topical creme industry.[62] Compounding pharmacies cater to physicians' and the public's interest in offering a simple treatment with few restrictions on use and a low incidence of side effects. The most common drugs in topical creme preparations were the NSAIDs. Now, ketamine, clonidine, gabapentin, and lidocaine are mixed upon request to treat neuropathic and referred pain and hyperesthetic areas (as in patients with post-herpetic neuralgia). Given the diverse effects of ketamine, its use in neuropathic pain (including central pain, complex regional pain syndrome [CRPS], fibromyalgia, and ischemic pain) has recently been reviewed.[63] Further clinical research will further define the usefulness of this drug.
The current concept of neuropathic pain is that nervous system malfunction is induced by high-intensity inflammatory pain or low-intensity neuropathic pain with which continuous noxious input is implied. In general, laboratory and clinical data confirm evidence that the noxious input from the neuropathic pain focus resembles abnormal epileptiform activity.[11] [14] [15] [18] [21] [23] [64] Backonja's review of this topic provides insight into the historical use of carbamazepine up to the modern-day use of evolutionary drugs in this class such as gabapentin, oxcarbazepine, and zonisamide.[64] Gabapentin's role in decreasing pain associated with postherpetic neuralgia, diabetic neuropathy, multiple sclerosis, and cancer-related neuropathic pain was documented by Mao and Chen.[65] They noted that benefits included reduction of paroxysmal burning, lancinating pain and of the allodynia to cold and light touch, perhaps due to the drug's effect on blocking calcium channels in the CNS and thereby decreasing central sensitization. In focusing on a more common form of neuropathic pain, postherpetic neuralgia, Singh and Kennedy reported benefit in pain reduction over two months.[66] However, they recommended comparative studies with other antiepileptic drugs to more clearly establish the longevity of the benefits and the optimal dosing. This is a frequently stated commentary in studies of antiepileptic drugs in the management of neuropathic pain, reflecting the reality that we are still learning about the precise mechanisms involved against which specific drugs from this class will be helpful.[23] [60] [67] In general, the drugs are added to an otherwise stable treatment regimen and the dose increased until there is either a positive effect on the pain or the onset of side effects (typically sedation or dizziness). Then decisions must be made whether to settle back to the last-tolerated dose and whether there is enough positive impact on the pain to warrant continued use. Although there may be less use of intravenous lidocaine infusions today to predict the benefit from anti-epileptic drugs,[60] some patients may benefit from the subsequent use of mexiletine.[67]
The pharmacologic treatment of neuropathic pain continues to evolve. As we understand more exactly the relevant mechanisms of this type of pain and the nuances of genomics and molecular pharmacology, drugs that target specific receptors and pathways will be developed. For example, not only does gabapentin increase γ-aminobutyric acid (GABA) levels, it also decreases levels of the primary excitatory neurotransmitter glutamate and has positive pain actions at N and P calcium channels.[68] [69] Topiramate is a new antiepileptic drug that also increases GABA levels and acts on sodium channels and also has actions at AMPA and kainate receptors, which suggests possible benefits in patients with inflammatory pain.[64]
It is tempting to believe that patients with refractory pain will become depressed.[27] [33] Treatment with antidepressants led to improvements in patients' pain, although the depression did not necessarily change, at least not as quickly.[8] [12] [16] [40] [70] Eventually, it was understood that old-fashioned tricyclic antidepressants such as amitriptyline and doxepin, which blocked the reuptake of serotonin and/or norepinephrine at the synaptic cleft, produced analgesia, even before any change in depression was manifested.[60] [70] This class of drugs gained wide application in the management of patients with neuropathic pain, usually in combination with antiepileptic drugs and mild to moderate analgesic medications. That some of the available drugs, most notably amitriptyline, had a sedating side effect was taken advantage of for patients with pain-related insomnia. Doses (i.e., 10 to 75 mg of amitriptyline) less than used to treat outright depression were reasonably well tolerated; because some patients developed anticholinergic side effects and weight gain, nortriptyline was used as well. Desipramine, the demethylated compound of imipramine, was another positive choice with fewer anticholinergic, sedating, and weight gain side effects. It is now appreciated that these drugs block sodium channels and manifest local anesthetic properties, giving insight into additional potential mechanisms for the neuromodulatory effects of these drugs. They are always listed as effective treatments in the management of postherpetic neuralgia.[71] [72]
Because of the side effect profile, much use of the serotonin selective reuptake inhibitor (SSRI) class of antidepressants has occurred.[60] [70] [73] These drugs block the reuptake of serotonin, a potent and prevalent inhibitory neurotransmitter in the nervous system, suggesting a high degree of benefit for patients with neuropathic pain. This is not widely manifested, perhaps because there isn't a matching of serotonin reuptake inhibition with receptor kinetics that lead to a benefit in patients with neuropathic pain. There is a clinically recognized discontinuation syndrome associated with these drugs.[74]
Patients with neuropathic pain may have a mixture of emotions including anxiety and depression.[27] [28] Many report pain-related insomnia for which additional medications are requested. It is important to ascertain in the evaluation of the patient whether a sleep disturbance was present prior to the onset of neuropathic pain. If this is found to be true, more realistic expectations about response to treatment for neuropathic pain will allow temperance for the clinical result. The tricyclic antidepressants have a definite contribution as sleep aids, more so than most of the SSRIs.[60] [70] In days gone by, antihistamines were used concurrently with analgesics to provide sedation, and the benzodiazepines have long been used. [60] If medications of this last-mentioned class are necessary in patients with neuropathic pain, Klonopin has been shown to be the drug of choice, as its use modifies aspects of neuropathic pain. This reality supports a fundamental principle of pain management: in order to simplify the medication component of the treatment program, medications that have more than one effect (e.g., tricyclic antidepressants to aid sleep at night and potentiate analgesia all day) should be chosen. The use of zolpidem is reasonable in patients with neuropathic pain, although the patient may find only a 3- to 4-hour sleep benefit. Repeating a small dose in the middle of the sleep session may be advantageous but may also risk morning fatigue.
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