Neuropathic Cancer Pain: The Role of Adjuvant Analgesics

The article by Drs. Farrar and Portenoy reviews thedefinition, clinical characteristics, mechanisms, and analgesic medicationoptions for neuropathic pain associated with cancer or its treatment. Theauthors have succinctly summarized decades of clinical research in what hasgrown into an enormously complex area.

There is indeed a dizzying array of analgesic options available for thetreatment of cancer-related neuropathic pain (about 50 drugs are listed in thearticle). Many agents are described as having wide dose ranges, with up to a40-fold difference between the lowest and highest effective dose. Sevendifferent routes of drug administration are mentioned in the article, and manyclinicians would add even more to that list.

This information, though complex, can be even more challenging to apply: Mostanalgesic drugs will need to be slowly dosed upward until pain relief or drugtoxicity occurs. If toxicity develops without adequate pain relief, the firstdrug should be tapered, another adjuvant should be selected, and the upwardstitration process repeated. Indeed, the key to successful application ofadjuvant analgesics in cancer-related neuropathic pain often requires patienceand endurance on the part of both the patient and physician in undergoingsequential and often toxic trials of analgesics.

Therein lies the art of neuropathic cancer pain management: which drug, forwhich patient, at which dose, and for how long?

Guideposts for managing neuropathic pain often lie hidden within the patient’sclinical presentation, and a brief attempt to summarize some of this informationfollows.

The Patient’s History

The patient’s history can help to elucidate the complex tapestry of painthat contributes to the overall experience of cancer-related neuropathic pain.Irrespective of the mechanism, neuropathic pain is often experienced as a blendof three different variations: (1) steady and burning; (2) sudden, stabbing, andbrief ("neuralgic"); and (3) hurts with light touch ("allodynia").For steady pain, an opioid or a tricyclic is often prescribed; for neuralgicpain, either carbamazepine or gabapentin (Neurontin) is administered; and forallodynia, a topical local anesthetic cream or hot pepper cream is generallyapplied, with or without concurrent administration of an oral tricyclic.

However, a common reason these drugs do not work is that the patient’shistory may have been misleading. Not all steady, burning pain is neuropathic;indeed, many chronic pains, particularly bone pain or muscle spasm, are commonlydescribed as steady and burning and often occur concurrently with cancer-relatedneuropathic pain. Brief, stabbing pain is a common experience with bonefracture, but may be distinguished from neuralgic pain because the latterusually occurs spontaneously (without being precipitated by movement) and in asequence of two or more brief pains in a row. Also, pain with light touch is notalways allodynia; it can be experienced if there is a sensitive structure underthe skin such as an infection or metastasis.

In addition, other aspects of the patient’s history can be helpful indirecting the overall analgesic strategy. Patient comorbidity can significantlyinfluence drug selection. For example, does the patient have dry mouth fromopioid use, radiotherapy, or for other reasons? Is there constipation, anorexia,confusion, postural hypotension, low energy, or gait trouble? How many pills perday is the patient already consuming? Is there a risk that the new analgesicwill add to existing drug toxicity? How taxed is the patient’s or caregiver’swillingness to add to the existing regimen? Could the patient also be depressed?Is it physically difficult for the patient to return to the clinic for severalfollow-up visits?

The Physical Examination

The physical examination can be of further help in directing an analgesicstrategy. About half of patients with cancer-related neuropathic pain havecontiguous muscle spasms,[1] and identification of a mixed pain mechanism, (inthis case both somatic and neuropathic) broadens the scope of possible treatmentto include modalities such as stretching, heat, cold, limb immobilization,transcutaneous electrical nerve stimulation (TENS), or nonsteroidalanti-inflammatory or other medications. Gentle stimulation of muscles or otherpotential pain-sensitive structures during the physical examination mayreproduce the pain that prompted the patient to seek medical attention and,thereby, help elucidate the components of a regional pain syndrome.

Further information gleaned from the physical examination that may help guidetreatment includes a determination of the stage of the cancer, and whether thereis extensive liver or lung disease. If the latter is true, there may not beenough time remaining for the patient to undergo lengthy dose escalation.Lamotrigine (Lamictal) can be administered for up to 2 months before thetarget dose (in the vicinity of 400 mg daily) is reached, and tricyclics andgabapentin may require several weeks or longer to reach the higher end ofdosing. Although phenytoin may be less reliably effective than the abovemedications, an oral loading dose can be administered within 24 hours or anintravenous loading dose in 30 minutes. If the patient has cachexia, liver pain,chronic obstructive lung disease or bone pain, there may be added reason toconsider corticosteroids for the neuropathic pain.

Once the history, physical examination, and all other investigations havebeen completed, the pain diagnosis can be formulated. If active cancer iscontributing significantly to the neuropathic pain, a course of radiationtherapy, corticosteroids, or opioids can be helpful.

A decade ago, investigators theorized that a mechanistic approach to themanagement of neuropathic pain could be developed.[2] Some inroads to thisapproach have been made over the past 10 years, with research involving sodiumchannels,[3] NMDA receptors,[4] and other pathophysiologically based approachesto pharmacologic intervention. Clearly, further work in this area is needed.

Conclusions

For most patients today, the management of cancer-related neuropathic cancerpain is based on comprehensive patient assessment, which usually points to a fewbest choices of adjuvant analgesics from among the many available (onemedication is introduced at a time through a trial-and-error approach). Successdepends on careful drug selection that is appropriate to the patient’s uniquepain and overall clinical situation. A supportive doctor-patient relationship isneeded, over time, for the patient to endure the upward titration of dose untileither pain relief or toxicity manifest.

Drs. Farrar and Portenoy have nicely summarized clinically relevantinformation on patient assessment and drug selection for cancer-relatedneuropathic pain, and more lengthy reference material on the assessment anddiagnosis of patients with neuropathic pain is available for those interested infurther detail.[5] What can be more challenging is the patient-focusedapplication of this information, and therein lies the art and challenge ofneuropathic cancer pain management.

References:

1. Hagen NA: Reproducing a cancer patient’s pain on physical examination:Bedside provocative maneuvers. J Pain Symptom Manage 18(6):406-411, 1999.

2. Max MB: Towards physiologically based treatment of patients withneuropathic pain. Pain 42:131-137, 1990.

3. Max MB, Hagen NA: Do changes in brain sodium channels cause central pain?(editorial) Neurology 54:544-545, 2000.

4. Fisher K, Coderre T, Hagen NA: Targeting the N-methyl-D-aspartate receptorfor chronic pain management: Preclinical animal studies, recent clinicalexperience, and further research directions. J Pain Symptom Manage20(5):358-373, 2000.

5. Portenoy RK: Adjuvant analgesics in pain management, in Doyle D, Hanks G,MacDonald N (eds): Oxford Textbook of Palliative Medicine, 2nd ed,pp 361-390. New York, Oxford University Press, 1998.