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Online pain mediation Conventional stationary pharmacies usually have controlled distribution systems from the manufacturer. Validation (drug manufacture) and Good distribution practices are followed. Home delivery of pharmaceuticals can be a desirable convenience but sometimes there can be problems.

The shipment of drugs through the mail and parcel post is sometimes a concern for temperature-sensitive pharmaceuticals. Uncontrolled shipping conditions can include high and low temperatures outside of the listed storage conditions for a drug. For example, the US FDA found the temperature in a mail box in the sun could reach 136°F (58°C) while the ambient air temperature was 101°F (38°C)[1]

Shipment by express mail and couriers reduces transit time and often involves delivery to the door, rather than a mail box. The use of insulated shipping containers also helps control drug temperatures, reducing risks to drug safety and efficacy.

Risks and concerns

  • Illegal or unethical pharmacies sometimes send outdated, substituted, or counterfeit medications[2][3][4]
  • Sometimes an online pharmacy may not be located in the country that is claimed. For example, one study of drug shipments claiming to be from Canada revealed many actually originated in several different countries and were often bogus medications[5]
  • Minors or children can order controlled substances without adult supervision.
  • Other concerns include potential lack of confidentiality, improper packaging, inability to check for drug interactions, and several other issues.[6]

Discussion

Legitimate mail-order pharmacies are somewhat similar to community pharmacies; one primary difference is the method by which the medications are requested and received. Some customers consider this to be more convenient than traveling to a community drugstore, in the same way as ordering goods online rather than going to a shop.[7]

While many internet pharmacies sell prescription drugs only with a prescription, some do not require a pre-written prescription. In some countries, this is because prescriptions are not required. Some customers order drugs from such pharmacies to avoid the inconvenience of visiting a doctor or to obtain medications their doctors were unwilling to prescribe. People living in the United States and other countries where prescription medications are very expensive may turn to online pharmacies to save money. Many of the reputable websites employ their own in-house physicians to review the medication request and write a prescription accordingly. Some websites offer medications without a prescription or a doctor review. This practice has been criticized as potentially dangerous, especially by those who feel that only doctors can reliably assess contraindications, risk/benefit ratios, and the suitability of a medication for a specific individual.[8] Pharmacies offering medication without requiring a prescription and doctor review or supervision are sometimes fraudulent and may supply counterfeit—and ineffective and possibly dangerous—medicines.

International consumers

International consumers sometimes purchase drugs online from online pharmacies in their own countries, or those located in other counties. Some of these pharmacies require prescriptions, while others do not. Of those that do not require prescriptions, some ask the customer to fill in a health questionnaire with their order. Many drugs available online are produced by well-known manufacturers such as Pfizer, Wyeth, Roche, and generic drugmakers Cipla and Ranbaxy of India and Teva Pharmaceutical Industries of Israel.

 U.S. consumers

An attraction of online pharmacies is drug prices. Shoppers can sometimes obtain 50 to 80 percent or more savings on U.S. prices at foreign pharmacies.[9]

The Washington Post reported that “…millions of Americans have turned to Mexico and other countries in search of bargain drugs…U.S. Customs estimates 10 million U.S. citizens bring in medications at land borders each year. An additional 2 million packages of pharmaceuticals arrive annually by international mail from Thailand, India, South Africa and other points. Still more packages come from online pharmacies in Canada.”[10]

Some people[opinion] in the US, including some legislators, favor accessing foreign-made prescription drugs to lower Americans’ health costs. According to a Wall Street Journal/Harris Online poll in 2006, 80 percent of Americans favor importing drugs from Canada and other countries.[11] President Obama’s budget supports a plan to allow people to buy cheaper drugs from other countries.[12] A report in the journal Clinical Therapeutics found that U.S. consumers face a risk of getting counterfeit drugs because of the rising Internet sales of drugs, projected to reach $75 billion by 2010.[13]

In the United States, there are two verification programs for online pharmacies that are recognized by the National Association of Boards of Pharmacy (NABP). One is the Verified Internet Pharmacy Practice Sites Program (VIPPS), which is operated by the NABP and was created in 1999.[14] The Food and Drug Administration refers Internet users interested in using an online pharmacy to the VIPPS program.[15] The other is LegitScript, which as of September 2010 had approved over 340 Internet pharmacies as legitimate and identified over 47,000 “rogue” Internet pharmacies.[16]

Overseas online pharmacies and U.S. law

Legality and risks of purchasing drugs online depend on the specific kind and amount of drug being purchased.

  • It is illegal to purchase controlled substances from an overseas pharmacy. A person purchasing a controlled substance from such a pharmacy may be violating two federal laws that carry stiff penalties. The act of importation of the drug from overseas violates 21 USC, Section 952 (up to 5 years in prison and $250,000 fine for importation of non-narcotic Schedule III, IV, or V drugs; possibly more for narcotics and Schedule I and II drugs). The act of simple possession of a controlled substance without a valid prescription violates 21 USC, Section 844 (up to 1 year in prison and $1,000 fine). FDA does not recognize online prescriptions; for a prescription to be valid there must be a face-to-face relationship between the patient and the health-care professional prescribing the drug. What exactly constitutes a “face-to-face” relationship is considered by many online pharmacies to be a subjective definition that would allow them to operate as an adjunct to the patient’s own physician if the patient submits medical records documenting a condition for which the requested medication is deemed appropriate for treatment. Sections 956 and 1301 provide exemptions for travellers who bring small quantities of controlled substances in or out of the country in person, but not by mail.
  • Importation of an unapproved prescription drug (not necessarily a controlled substance) violates 21 USC, Section 301(aa), even for personal use.[17] The Food, Drug, and Cosmetic Act does allow for the importation of drug products for unapproved new drugs for which there is no approved American version. However, this allowance does not allow for the importation of foreign-made versions of U.S. approved drugs.
  • The law further specifies that enforcement should be focused on cases in which the importation by an individual poses a threat to public health, and discretion should be exercised to permit individuals to make such importations in circumstances in which the prescription drug or device imported does not appear to present an unreasonable risk to the individual.[18]
  • It is also illegal to import non-approved drugs (21 USC sections 331(d) and 355(a)); however, FDA policies suggest that, under certain circumstances, patients may be allowed to keep these drugs.[19]
  • Individual U.S. states may implement their own laws regulating importation, possession, and trafficking in prescription drugs and/or controlled substances.[citation needed]
  • For several years, the states of Nevada, Minnesota, Illinois and Wisconsin have run official state programs to help their residents order lower-cost drugs from abroad to save money.[citation needed]

Enforcement

  • Any package containing prescription drugs may be seized by US Customs and Border Protection. The package may be held and eventually returned to the sender if the addressee does not respond and provide proof that they are allowed to receive these drugs (e.g., a valid prescription).[20] In practice, the number of packages containing prescription drugs sent to United States on a daily basis far exceeds CBP’s capabilities to inspect them.[21] In the past, packages often passed through customs even if they were not sent from Canada or otherwise didn’t meet the requirements of section 804 of 21 USC. Until recently, about 5 percent of prescription drug packages sent from Canada were being seized.[22]
  • DEA and FDA[23] generally do not target consumers unless drugs are imported in large quantities (suggesting intent to distribute) or represent a perceived danger to public health (opiates, amphetamines).
  • Rarely, drug importation laws are enforced on the local level. For example, in June 2005 in Baton Rouge, Louisiana, a number of customers of online pharmacies were arrested by local law enforcement officers and charged with possession of a controlled substance without prescription.[24]

UK consumers

In the UK more than 2m people buy drugs regularly over the internet from online pharmacies; some are legitimate but others have “dangerous practices” that could endanger children.[25] In 2008, the RPSGB introduced a green cross logo to help identify accredited online pharmacies (from 2010 the internet pharmacy logo scheme is run by the GPhC).[26]

European registered pharmacists have reciprocal agreements allowing them to practice in the UK by simply getting registered with the General Pharmaceutical Council.

The first internet pharmacy in the UK was Pharmacy2U, which started operating in November 1999.[27] The UK is a frontline leader in internet pharmacy since the law change in 2005 that made it legal for pharmacies to sell over the Internet.[citation needed]Drugs supplied in this way tend to be medicines which doctors refuse to prescribe for patients, or would charge a private prescription fee, as all patients treated under the National Health Service pay either a low flat price or nothing for prescribed medicine (except for medicine classed as lifestyle medicine, eg: anti-malarials for travel), and medical equipment.[citation needed]

In the UK, online pharmacies often link up with online clinic doctors. Doctors carry out online consultations and issue prescriptions.[28] The company employing the doctors must be registered with the Care Quality Commission. Online clinics only prescribe a limited number of medicines and do not replace regular doctors working from surgeries. There are various ways the doctors carry out the online consultations; sometimes it is done almost entirely by questionnaire. Customers usually pay one fee which includes the price of the consultation, prescription and the price of the medicine.

Combination analgesics in adults

Bridin P Murnion, Staff Specialist, Drug Health Service, Royal Prince Alfred Hospital, Sydney

Summary

Many analgesic products contain combinations of different drugs.There are few direct comparisons of these combinations, but several appear to be no more effective than an appropriate dose of one of their individual analgesic components. Many combinations should be avoided because they contain drugs that have significant adverse effects or that do not contribute to the analgesic effect. Some combinations can be obtained without a prescription. Patients may inadvertently overdose themselves if they take several of these products simultaneously.

Key words: aspirin, codeine, dextropropoxyphene, NSAIDs, paracetamol.

(Aust Prescr 2010;33:113-5)

Introduction

There are at least 40 different combination analgesic preparations available in Australia. Most of these are combinations of paracetamol 500 mg with codeine in doses ranging from 8 mg to 30 mg.1 A number of preparations also contain doxylamine, a sedating antihistamine with anticholinergic effects.2There are also other preparations available which contain paracetamol and dextropropoxyphene, aspirin and codeine, aspirin and dihydrocodeine, and ibuprofen and codeine.1 Internationally, preparations containing paracetamol with other opioids such as oxycodone and tramadol are available.

Regulation

The Australian scheduling of combination analgesics under poisons regulations is determined by the dose of codeine per tablet, the number of tablets in a pack, and the other drugs in the combination (for example doxylamine). All preparations containing 30 mg codeine in combination with paracetamol or aspirin are Schedule 4. They therefore require a prescription. Preparations with doses of codeine 15 mg or less have been available as Schedule 2 (pharmacy medicine) or 3 (pharmacist-only medicine), but from 1 May 2010 they were no longer available in Schedule 2. Combination analgesics containing up to 12 mg codeine are pharmacist-only, and those containing more than 12 mg are prescription-only. The pharmacist-only products are limited to no more than five days of treatment.3

Evidence of efficacy

Paracetamol or a non-steroidal anti-inflammatory drug (NSAID) given with a strong opioid such as morphine in a multimodal analgesic regimen for acute pain, reduces the amount of opioid used, improves analgesia and reduces the duration of patient-controlled analgesia.4 However, data supporting products which combine a weak opioid, such as codeine, with paracetamol or an NSAID, are limited. There is much variability in the dose of weak opioid contained in combination products, and the role of codeine in managing acute pain is unclear. Analgesic guidelines state that ‘although codeine is widely used, its place in therapy is uncertain’.5The National Prescribing Service (NPS) has stated that ‘studies in acute pain suggest only modest additional analgesic efficacy when a weak opioid is added to paracetamol, but a higher rate of adverse effects after repeated doses’.6There is consensus that paracetamol is the first-line treatment for many acute pain states.4–8

The Oxford Pain group has developed a league table of analgesic efficacy for most common oral analgesics. This uses data from systematic reviews of randomised, double-blind, single-dose studies of patients with moderate to severe pain where the outcome is a reduction of pain by at least 50% in 4–6 hours. Data are expressed as:

  • the number of patients who need to be treated (NNT) for one to get 50% relief
  • the percentage of patients with at least 50% pain relief (Table 1).

There are limitations to these data. Often the trial sample size is small so there may be wide confidence intervals, they are not head-to-head comparisons, adverse events are not reported and the trials are single-dose studies. The table does not contain information about all the analgesic combinations available in Australia, and includes information about products which are not available here. However, the table provides the best available comparative information.9

Table 1
Efficacy of oral analgesics *
Analgesic (mg) Number of patients in comparison Percent with at least 50% pain relief NNT † Confidence intervals
Paracetamol 1000 + codeine 60 197 57 2.2 1.7–2.9
Paracetamol 600/650 + codeine 60 1123 42 4.2 3.4–5.3
Paracetamol 300 + codeine 30 379 26 5.7 4.0–9.8
Paracetamol 500 + oxycodone IR 10 315 66 2.6 2.0–3.5
Paracetamol 500 + oxycodone IR 5 150 60 2.2 1.7–3.2
Paracetamol 325 + oxycodone IR 5 149 24 5.5 3.4–14.0
Paracetamol 650 + tramadol 75 679 43 2.6 2.3–3.0
Paracetamol 650 + dextropropoxyphene (65 mg hydrochloride or 100 mg napsylate) 963 38 4.4 3.5–5.6
Aspirin 650 + codeine 60 598 25 5.3 4.1–7.4
Aspirin 600/650 5061 38 4.4 4.0–4.9
Codeine 60 1305 15 16.7 11–48
Paracetamol 1000 2759 46 3.8 3.4–4.4
Tramadol 100 882 30 4.8 3.8–6.1
Ibuprofen 200 3248 48 2.7 2.5–2.9
* Modified from the Oxford league table 9
Numbers needed to treat (NNT) are calculated for the proportion of patients with at least 50% pain relief over 4–6 hours compared with placebo in randomised, double-blind, single-dose studies in patients with moderate to severe pain
IR Immediate-release formulation

Paracetamol with codeine

A Cochrane review found that paracetamol with codeine is more effective in acute postoperative pain than paracetamol alone. The NNT to achieve 50% pain relief at 4–6 hours was 2.2 for paracetamol 1 g with codeine 60 mg. Paracetamol 1 g alone has an NNT of 3.8, but paracetamol 600 mg in combination with codeine 60 mg has an NNT of 4.2.9,10 Although the dose of codeine required to provide any analgesic effect is unclear, it is believed that a minimum dose of 30 mg codeine is required. The majority of combination products available in Australia contain doses of codeine less than this.5

In contrast, the National Health and Medical Research Council review of evidence for the management of acute musculoskeletal pain said that there is insufficient evidence to recommend the use of opioids or compound analgesics (paracetamol/codeine combinations) in acute low back pain, acute neck pain, acute shoulder pain or acute knee pain. It reports that, in general, opioids and compound analgesics have a substantially increased risk of adverse effects compared with paracetamol alone.7

For dental pain, the most effective approach is to undertake appropriate dental treatment. After dental extraction the efficacy of NSAIDs is superior to that of combinations of paracetamol and codeine.11,12 The Therapeutic Guidelines: Oral and Dental recommend that if a combination is used, the dose of codeine should be at least 25 mg and suggest that a codeine dose of 60 mg with paracetamol 1 g will be required for severe dental pain.11

Dextropropoxyphene

Overdoses of dextropropoxyphene can be fatal. There are concerns about accumulation of a toxic metabolite of dextropropoxyphene in patients with renal impairment.5The drug has been withdrawn in the UK and is being withdrawn in New Zealand. Dextropropoxyphene is a weak opioid, but in combination with paracetamol it provides no increase in analgesia and has more adverse effects than paracetamol alone.5 The Oxford league table shows that dextropropoxyphene 65 mg in combination with paracetamol 650 mg has an NNT of 4.4.9

Doxylamine

There is no evidence that doxylamine has any analgesic efficacy, but this sedating antihistamine may be a component of compound analgesics. Doxylamine may be subject to abuse and combination analgesic preparations containing it cannot be recommended.

Opioids in combination with NSAIDs

While there is a significant body of evidence identifying the efficacy of NSAIDs in acute pain, there are limited data on combining them with opioids. Many NSAIDs, in single-dose studies, show greater efficacy than codeine in combination with paracetamol or codeine in combination with aspirin.9 Aspirin 650 mg in combination with codeine 60 mg is effective in postoperative pain with an NNT of 5.3 for at least 50% pain relief over 4–6 hours in patients with moderate to severe pain compared with placebo. This appears to be less effective than a 650 mg dose of aspirin alone (NNT 4.4) but the statistical confidence intervals overlap.9 Codeine 60 mg may enhance the analgesic effect of ibuprofen 400 mg, however data are lacking to compare the Australian formulation of codeine 12.8 mg with ibuprofen 200 mg to ibuprofen 200 mg alone.13

Chronic pain

The evidence for long-term efficacy of opioids in chronic pain is limited. Opioids should only be considered as a component of a multidimensional management plan. In general, opioids other than codeine should be chosen. One exception is osteoarthrosis of the hip, for which there is some evidence for efficacy of codeine.5

Opioid analgesics should be avoided in headache because of the risk of dependence and medication overuse headache.4,8

Adverse effects and toxicity

Opioids and compound analgesics have a substantially increased risk of adverse effects compared with paracetamol alone.7These adverse effects include constipation, nausea, vomiting and drowsiness. The elderly appear to be more susceptible to adverse effects.5 Abuse of, and dependence on, codeine-containing combination analgesics is a poorly quantified, but likely significant, risk.14 Codeine is converted to morphine by cytochrome P450 2D6, but 7–10% of the Caucasian population lack this enzyme. These ‘poor metabolisers’ of codeine will get no analgesic benefit, but may experience adverse effects.5

A significant proportion of cases of acute liver failure are from unintentional paracetamol overdose. Many of these patients have taken more than one paracetamol-containing preparation simultaneously.15

Conclusion

In summary, for acute postoperative pain there is evidence of efficacy for paracetamol 1 g with codeine 60 mg, and some evidence for paracetamol combined with codeine in hip osteoarthroses. Current guidelines do not support the use of paracetamol and codeine combination products in other acute or chronic pain states. There are limited data for doses of codeine less than 60 mg in combination with paracetamol, and current data suggest that paracetamol alone has greater efficacy than paracetamol combined with codeine at doses under 60 mg. Current evidence shows improved analgesia with codeine 60 mg and ibuprofen 400 mg compared to ibuprofen alone, but there are minimal data for lower doses. Indirect comparisons show that the combination of aspirin and codeine may be less efficacious than aspirin alone and therefore the combination cannot be recommended. Given the lack of documented analgesic efficacy of low-dose codeine preparations, rescheduling of codeine in Australia is unlikely to impact significantly on analgesic options, but may reduce the harms from overuse.

References

  1. Australian register of therapeutic goods. http://www.tga.gov.au/docs/html/artg.htm [cited 2010 Apr 16]
  2. Sweetman SC, editor. Martindale: The complete drug reference. 36th ed. London: Pharmaceutical Press; 2009.
  3. Therapeutic Goods Administration. Codeine rescheduling – information for sponsors. 24 February 2010 .www.tga.gov.au/npmeds/codeine.htm [cited 2010 Jul 7]
  4. National Health and Medical Research Council. Acute pain management: scientific evidence. 3rd ed. Canberra: NHMRC; 2010. http://www.nhmrc.gov.au/publications/synopses/cp104syn.htm [cited 2010 Jul 7]
  5. Getting to know your drugs. In: eTG Analgesic. Melbourne: Therapeutic Guidelines Limited; 2007.
  6. National Prescribing Service (NPS). Analgesic options for pain relief. NPS News 47. 2006.www.nps.org.au/news_47 [cited 2010 Jul 7]
  7. National Health and Medical Research Council. Evidence-based management of acute musculoskeletal pain. Canberra: NHMRC; 2003. http://www.nhmrc.gov.au/publications/synopses/cp94syn.htm [cited 2010 Jul 7]
  8. National Prescribing Service (NPS). Headache and migraine. NPS News 38. 2005. http://www.nps.org.au/news_38 [cited 2010 Jul 7]
  9. Bandolier. Oxford league table of analgesics in acute pain. 2007. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html [cited 2010 Jul 7]
  10. Toms L, Derry S, Moore RA, McQuay HJ. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults. Cochrane Database Syst Rev. (1):CD001547, 2009.
  11. Opioids. In: eTG Oral and Dental. Melbourne: Therapeutic Guidelines Limited; 2007.
  12. Abbott PV. Medical management of dental and oral pain. Aust Prescr 2007;30:77-9.
  13. Po AL, Zhang WY. Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis. Eur J Clin Pharmacol 1998;53:303-11.
  14. Brands B, Blake J, Sproule B, Gourlay D, Busto U. Prescription opioid abuse in patients presenting for methadone maintenance treatment. Drug Alcohol Depend 2004;73:199-207.
  15. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multi center, prospective study. Hepatology 2005;42:1364-72.
  16. Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound

    Background: Flupirtine is a nonopioid drug without antipyretic or antiphlogistic properties and with a favorable tolerability. It constitutes a unique class within the group of nonsteroidal analgesics and displays a peculiar pharmacodynamic profile that invites the investigation of applications beyond the pain-relieving effect. Objective: This review describes and evaluates the pharmacologic and clinical literature regarding flupirtine and discusses its future potential. Methods: A search of the primary literature and conference abstracts was conducted using the keyword ‘flupirtine’. Resulting articles were compiled and analyzed for this review. Results/conclusions: Although flupirtine has gained a firm place in the treatment of acute and chronic pain in various clinical settings since its introduction, a broader range of applications remains to be explored in clinical trials. Possible neuroprotective effects due to N-methyl-d-aspartate antagonistic properties of flupirtine might be promising in the treatment of Creutzfeld–Jakob disease, Alzheimer’s disease, and multiple sclerosis. Trials in these fields are forthcoming.
    DIAGNOSIS AND ASSESSMENT

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     • Introduction
     • Diagnosis and assessment
     • Pathophysiologic mechanisms
     • Treatment recommendations
     • Conclusions
     • Author information
     • References


    Neuropathic pain syndromes typically have both negative andpositive sensory symptoms and signs.3 Nonsensory neurologicalsymptoms and signs depend on the underlying cause and may independentlycontribute to pain and disability. Although neuropathic painhas been defined by the International Association for the Studyof Pain as pain “initiated or caused by a primary lesion ordysfunction in the nervous system,”4(p212) several investigatorshave recently argued that the inclusion of the term dysfunctionmakes this definition vague and unacceptably broad.5-6 A proposedsolution is to define neuropathic pain as pain caused by a lesionof the peripheral or central nervous system (or both) manifestingwith sensory symptoms and signs.6 Underlying causes includeinfections, trauma, metabolic abnormalities, chemotherapy, surgery,irradiation, neurotoxins, inherited neurodegeneration, nervecompression, inflammation, and tumor infiltration. Demonstratinga lesion of the nervous system compatible with particular symptomsand signs provides strong support for considering the pain tobe neuropathic. However, when no lesion can be demonstrated,the limits of current diagnostic technology do not always allowthe possibility of neuropathic pain to be excluded. The diagnosisof neuropathic pain is based on a medical history, review ofsystems, physical and neurological examination, and appropriatelaboratory studies including blood and serologic tests, magneticresonance imaging, and electrophysiologic studies.3 In someinstances, nerve or skin biopsy is necessary to directly visualizenerve fibers.
    Evaluation of Pain and Other Symptoms

    The assessment of pain and other symptoms is needed for diagnosisand to guide therapy. No single symptom or sign is pathognomonic.Because neuropathic pain is the result of disease or injuryto the nervous system, clinical manifestations typically includeboth negative and positive sensory symptoms and signs. Motorsymptoms and signs are often present, but these deficits canbe very subtle.

    A distinction should be made between stimulus-evoked pain andspontaneous (stimulus-independent) pain, which may have differentunderlying mechanisms.7 Spontaneous pain can be either constantor intermittent (even paroxysmal), and most patients describehaving both (eg, constant “burning” pain plus intermittent painthat is “shooting” or “electric shock–like”). In addition,spontaneous paresthesias and dysesthesias manifest as abnormalsensations, including crawling, numbness, itching, and tingling.When obtaining the patient’s history, it is important to assessthe intensity, quality, and duration of spontaneous pain andabnormal sensations. The topographical distribution is especiallyhelpful in guiding the neurological examination.

    Pain may be evoked by everyday environmental stimuli such asthe gentle touch and pressure of clothing, wind, riding in acar, and hot and cold temperatures. Common neurological examinationtools, including a cotton wisp, a foam brush, a tuning fork,and cold and warm water–filled tubes, can be used to mimicthese stimuli.

    Pain intensity can be rated with any of several reliable andvalidated verbal, numerical, or visual analog scales. Patientsrate their pain using some type of continuum (eg, “no pain”to “worst possible pain”).8 The often unusual abnormal sensationsin patients with neuropathic pain can be assessed with measuresof pain quality such as the Neuropathic Pain Scale9 and NeuropathicPain Questionnaire.10 Chronic pain has a significant negativeeffect on quality of life, and various measures of physicaland emotional function can also be used to evaluate a patient’sresponse to treatment.11 Assessment of psychological comorbidity(eg, depression or anxiety), sleep disturbance, work-relatedissues, treatment expectations, rehabilitative needs, and theavailability of social support from family and friends shouldnot be overlooked.12

    Physical Examination

    A thorough physical and neurological examination can help determinewhere the lesion is and assess nonneuropathic contributionsto the patient’s pain, most commonly musculoskeletal, inflammatory,myofascial, and psychological processes.3 When combined witha history and laboratory tests suggesting a specific cause,the finding of negative and positive sensory phenomena in thesame area innervated by damaged nervous system pathways usuallyconfirms the diagnosis.

    Patients may have sensory deficits with one modality, such aspinprick sensitivity, and hyperalgesia to another, such as lighttouch, in the same nerve distribution. Whereas the physicianmay have difficulty recognizing this paradoxical finding, patientsare even more confused by the complexity of their sensory experiences;they often have trouble describing the unusual nature of theirsymptoms and fear that they will not be believed. For patientsto be good sensory witnesses and provide all of the necessaryinformation, they need to be reassured as well as instructedto carefully describe their symptoms and rate the severity oftheir abnormal sensations. When specific stimuli in the standardneurological sensory examination are applied first to the unaffectedarea and then to the area affected by pain, patients shouldbe instructed to first respond in simple terms—that is,whether the stimulus applied to the painful area causes thesame sensation as in the unaffected area or whether it is lessor more intense—before describing their perception ofthe quality of the stimulus. For example, pinprick may be morepainful (hyperalgesia) but less sharp because of the underlyingsensory deficit.

    Pain in response to a normally nonnoxious stimulus is termedallodynia. Dynamic mechanical allodynia can be elicited by lightlyrubbing or brushing the skin with a cotton swab or brush, staticmechanical allodynia can be provoked by blunt pressure witha finger, and thermal allodynia can be assessed with a warmor cool tuning fork. An increased sensation of pain in responseto a normally painful stimulus is termed hyperalgesia, whichcan be assessed using painful thermal (cold or heat) or punctate(eg, pinprick) stimuli. Painful summation and hyperpathia torepeated stimuli, especially when the initial sensation is reduced,is important evidence of abnormal sensory processing.

    Nonsensory neurological and musculoskeletal symptoms may contributestrongly to overall disability. Motor system symptoms and signsinclude weakness, fatigability, hypotonia, tremor, dystonia,spasticity, ataxia, apraxia, and motor neglect. Other musculoskeletalsymptoms and signs include decreased range of motion, stiffnessof joints, spontaneous muscle spasms, localized muscle tenderness,and myofascial trigger points.

    Ancillary Studies

    There is no single diagnostic test for neuropathic pain or painin general. Ancillary studies can confirm or exclude underlyingcauses and suggest disease-specific treatments, such as fordiabetes mellitus in patients with painful neuropathy or spinaldisorders in patients with radiculopathy. To assess peripheralnerve function, nerve conduction velocity tests and electromyographyprovide information about large myelinated peripheral nervefunction but do not test smaller myelinated or unmyelinatednerve fibers carrying pain and temperature information. Quantitativethermal sensory testing relies on the patient’s psychophysicalability to discriminate between fine changes in thermal stimuli;it is not widely used because it requires specialized equipmentand training. Magnetic resonance imaging assesses anatomicalintegrity of thermonociceptive sensory-processing regions suchas the brainstem, thalamus, sensory cortex, anterior cingulate,and insular cortex, which can contribute to central neuropathicpain when injured. Functional magnetic resonance imaging canfurther assess these and other pain-related structures, butits role in clinical practice will remain limited in the nearfuture.

    Diagnosing neuropathic pain can be difficult. For example, inradicular neck and low back pain, there is a significant neuropathiccomponent from the nerve root injury, but mechanical instabilityor secondary myofascial pain may mask this component. Physiciansshould also keep in mind that psychosocial factors are a majorcomponent of the experience of chronic pain and should be routinelyaddressed when patients are evaluated. Psychological processessuch as anxiety can influence the report of pain and in rareinstances produce exaggerated responses. However, sincerelycommunicating that the patient’s pain is taken seriously andproviding clear instructions will minimize the possibility thatthe neurological examination is unreliable or uninterpretablebecause of psychological processes. When combined with a longhistory of multiple unexplained pain problems, somatizationdisorder or another psychiatric diagnosis is possible. Properdiagnosis is the cornerstone of effective treatment, and complexpatterns of signs and symptoms may necessitate the involvementof multiple medical specialties.


    PATHOPHYSIOLOGIC MECHANISMS

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     • Treatment recommendations
     • Conclusions
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    Our ability to translate pain complaints and sensory findingsinto specific pathophysiologic mechanisms that have treatmentimplications is in its infancy.13-16 Clinical investigationsof pain mechanisms are labor intensive and require specializedequipment; thus, they are not yet practical for routine clinicaluse. Even in specialized pain research settings, it is difficultto identify specific neuropathic pain mechanisms. A simple focalperipheral nerve injury unleashes a range of peripheral andcentral nervous system processes that can all contribute topersistent pain and abnormal sensation. Inflammation, reparatorymechanisms of neural tissues in response to injury, and thereaction of adjacent tissues to injury lead to a state of hyperexcitabilityin primary afferent nociceptors, a phenomenon termed peripheralsensitization. In turn, central neurons innervated by such nociceptorsundergo dramatic functional changes including a state of hyperexcitabilitytermed central sensitization. Normally these sensitization phenomenaextinguish themselves as the tissue heals and inflammation subsides.However, when primary afferent function is altered in an enduringway by injury or disease of the nervous system, these processespersist and may be highly resistant to treatment.

    Injury or permanent loss of primary afferent fibers (deafferentation)differentiates peripheral neuropathic pain from other typesof pain. Positive sensory phenomena (spontaneous pain, allodynia,and hyperalgesia) that are characteristic of patients with neuropathicpain are likely to have many underlying mechanisms, includingectopic generation of impulses as well as the de novo expressionof neurotransmitters and their receptors and ion channels. Directinjury to central structures may permanently alter sensory processing,and in some patients it causes central neuropathic pain anddysesthesias. The mechanisms underlying central neuropathicpain, however, are still unclear.

    An oversimplified but useful approach is to distinguish processesthat involve the following: (1) increased primary afferent nociceptorfiring (eg, as a result of abnormal collections of sodium channelsin damaged peripheral nerve fibers, causing ectopic discharge);(2) decreased inhibition of neuronal activity in central structures(eg, due to loss of inhibitory neurons); and (3) altered centralprocessing (central sensitization) so that normal sensory inputis amplified and sustained. A continuum that has been exploredin PHN has “irritability” of the nociceptive system at one endand deafferentation at the other.15-16 Although the ends ofthe continuum can be differentiated by clinical examinationand response to a brief focal application of topical capsaicin(capsaicin response test), the treatment implications of thisdifferentiation remain to be explored.17 The contributions ofother peripheral processes remain poorly understood. For example,the sympathetic nervous system may facilitate persistent abnormalprimary afferent nociceptor activity following nerve injury,18and nerve injury and inflammation during the acute phase ofherpes zoster may be followed by a mixture of abnormal regenerationand receptor expression and permanent cutaneous afferent lossin patients with PHN.19

    Although the many mechanisms identified in animal models ofneuropathic pain still require translation and confirmationin human neuropathic pain syndromes, the results from thesemodels provide valuable insights into diverse manifestationsof neuropathic pain. Human laboratory studies,20-22 althoughlimited in number, support the idea that the pathophysiologicmechanisms discovered in animal models are relevant to our understandingof human neuropathic pain.


    TREATMENT RECOMMENDATIONS

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    Members of the faculty of the Fourth International Conferenceon the Mechanisms and Treatment of Neuropathic Pain participatedin a meeting supported by an unrestricted educational grantto the University of Rochester Office of Professional Education(Rochester, NY) from Endo Pharmaceuticals (Chadds Ford, Pa)and contributed as authors to the preparation of this article.Specialties represented include anesthesiology, basic neuroscience,epidemiology, geriatrics, internal medicine, neurology, neurosurgery,outcomes research, pharmacoeconomics, and psychology. MEDLINEsearches, examination of reference lists of published articlesand book chapters, and personal knowledge of the literaturewere used to identify material relevant to developing treatmentrecommendations for patients with neuropathic pain. This materialincluded systematic literature reviews, reports of randomizedclinical trials, and publications discussing the developmentand evaluation of clinical guidelines.

    General Considerations

    To evaluate changes in pain intensity during treatment, an 11-pointnumerical rating scale in which 0 equals “no pain” and 10 equals”worst possible pain” is widely used to assess the patient’slevel of pain currently, during the past day, or during thepast week. Recent data suggest that a reduction of 30% on sucha scale is clinically important and equivalent to categoricalratings of “moderate relief” or “much improved.”23 The first-linetreatments discussed as follows have all been demonstrated toprovide statistically significant and clinically meaningfultreatment benefits compared with placebo in multiple randomizedcontrolled trials. Benefits of pharmacotherapy for improvingquality of life, including physical and emotional function,have been found less consistently than for reducing pain intensity.Although the efficacy of treatments have been compared by evaluatingthe number needed to treat,24-28 the small sample sizes andmethodological shortcomings of some trials limit confidencein such comparisons.

    Drug-related adverse effects are common in the treatment ofneuropathic pain, not only because of the specific medicationsused but also because many patients with this condition areolder, take other medications, and have comorbid illnesses.On the basis of our clinical experience and analyses of thenumber needed to harm,24-25,27 we considered safety, adverseeffects, and drug interactions in the development of our recommendations.

    Most randomized controlled trials of chronic neuropathic painhave examined only 2 pain syndromes, PDN and PHN. Moreover,the US Food and Drug Administration (FDA) has approved medicationsfor the treatment of only 2 specific neuropathic pain syndromes:trigeminal neuralgia (carbamazepine) and PHN (gabapentin andthe 5% lidocaine patch). The applicability of the results ofclinical trials for one chronic neuropathic pain syndrome toothers cannot be determined, but most of the first-line therapiesdiscussed as follows have been tested with multiple types ofneuropathic pain and have shown similar results.26 Medicationswith minimal risk that have demonstrated efficacy for 1 or more(ideally related) neuropathic pain syndromes are preferred.When efficacy has not been established, acceptable safety andtolerability in light of the patient’s medical condition, age,pain severity, and previous treatment history are paramount.

    Five caveats are required before presenting our treatment recommendations.First, these recommendations may apply to complex regional painsyndrome type I, although controlled trials of first-line medicationsare lacking; this pain syndrome is believed to be due to nervoussystem dysfunction without permanent injury to a nerve trunk.Second, although chronic neuropathic back pain (ie, cervicaland lumbar radiculopathic pain) is probably the most prevalentpain syndrome to which neuropathic mechanisms contribute, thereare no accepted diagnostic criteria for identifying this neuropathiccomponent. It is likely that a combination of neuropathic, skeletal,and myofascial mechanisms account for this type of pain in manypatients. Subgroup analyses of a randomized placebo-controlledtrial suggested that patients who had chronic radicular lowback pain responded best to treatment with nortriptyline hydrochloride,29one of the first-line medications discussed as follows. Third,distinct treatment guidelines for tic douloureux (trigeminalneuralgia) emphasize carbamazepine, phenytoin, and baclofen.30Fourth, we acknowledge that pharmacologic management is nota cure and should be considered an integral component of a morecomprehensive approach to treatment. A discussion of the manywidely used nonpharmacologic approaches including physical therapy,psychological treatments, invasive procedures (eg, neural blockadeor dorsal column stimulation), and various complementary andalternative medicine interventions is beyond the scope of thisreview. Fifth, we assume that pharmacotherapy will be used withina treatment context in which education, support, and reassurancecharacterize the relationship between the patient and physician.We strongly recommend that the dosage be adjusted as necessarybased on frequent and careful evaluation of adverse effects,treatment adherence, and pain relief.

    Review and Specific Recommendations

    Recommendations for first-line pharmacologic treatments arebased on positive results from multiple randomized controlledtrials, and recommendations for second-line pharmacologic treatmentsare based on the positive result of a single randomized controlledtrial or inconsistent results of multiple randomized controlledtrials (with 1 exception, discussed as follows). The resultsof published trials and our clinical experience provide thefoundation for our specific recommendations for first-line treatments.

    First-line Medications. The efficacy of gabapentin, the 5% lidocainepatch, opioid analgesics, tramadol hydrochloride, and tricyclicantidepressants (TCAs) has been consistently demonstrated inmultiple randomized controlled trials. Each one can be usedas an initial treatment for neuropathic pain in certain clinicalcircumstances. Opioid analgesics and TCAs generally requiregreater caution than the other options. For each of these 5medications, brief reviews of the relevant randomized clinicaltrials and specific treatment recommendations follow. Treatmentrecommendations are summarized in Table 2.

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    Table 2. First-line Medications for Neuropathic Pain

    Gabapentin. There are 8 published double-blind, placebo-controlledrandomized clinical trials of gabapentin for chronic neuropathicpain. These studies examined patients with PHN, PDN, mixed neuropathicpain syndromes, phantom limb pain, Guillain-Barré syndrome,and acute and chronic pain from spinal cord injury.31-38 Gabapentinat dosages up to 3600 mg/d significantly reduced pain comparedwith placebo; improvements in sleep, mood, and quality of lifewere also demonstrated in some trials. In 2 trials of PDN andspinal cord injury pain with small sample sizes or relativelylower dosages, evidence of efficacy was more limited.33, 38On the basis of the results of 2 large randomized trials,32,34the FDA approved gabapentin for the treatment of PHN.

    The adverse effects of gabapentin include somnolence and dizzinessand, less commonly, gastrointestinal symptoms and mild peripheraledema. All of these effects require monitoring and dosage adjustmentbut usually not discontinuation of the drug. Gabapentin maycause or exacerbate gait and balance problems as well as cognitiveimpairment in elderly patients, and dosage adjustment is necessaryin patients with renal insufficiency. However, its generallyexcellent tolerability, safety, and lack of drug interactionsdistinguish gabapentin from most other oral medications usedfor the treatment of chronic neuropathic pain.

    To decrease adverse effects and increase patient adherence totreatment, gabapentin should be initiated at low dosages—100to 300 mg in a single dose at bedtime or 100 to 300 mg 3 timesdaily—and then titrated every 1 to 7 days by 100 to 300mg as tolerated. Although 3 times daily is the target dosage,more rapid titration may be accomplished if most of the dailydose is initially given at bedtime to limit daytime sedation.Target dosages that demonstrated benefits of gabapentin treatmentfor neuropathic pain ranged from 1800 mg/d (the FDA-approveddosage for PHN) to 3600 mg/d. If only partial relief of painoccurs at 1800 mg/d, titration can be continued up to 3600 mg/d(1200 mg 3 times daily) as tolerated. The final dosage shouldbe determined either by achieving complete pain relief or bythe development of unacceptable adverse effects that do notresolve promptly. An adequate trial of gabapentin would include3 to 8 weeks for titration to allow the development of toleranceto adverse effects, plus 1 to 2 weeks at the maximum tolerateddosage.

    5% Lidocaine Patch. There are 2 published double-blind, randomized,vehicle-controlled clinical trials of the 5% lidocaine patchin patients with PHN.39-40 In these studies, patients obtainedstatistically significantly greater pain relief with the 5%lidocaine patch compared with vehicle-controlled patches containingno lidocaine. On the basis of these results, the FDA approvedthe 5% lidocaine patch for the treatment of PHN. Notably, theefficacy of this treatment has been demonstrated only in patientswith PHN and allodynia, and no controlled studies have beenconducted for other pain conditions. Anecdotal evidence of abeneficial effect in patients who have other types of neuropathicpain with allodynia has been published.41

    The 5% lidocaine patch is a topical preparation. In patientswith normal hepatic function, blood levels of the drug are minimal,and accumulation does not occur with a dosage schedule of 12hours on, 12 hours off. Because of this, the 5% lidocaine patchhas excellent safety and tolerability, and the only adverseeffects involve mild skin reactions (eg, erythema or rash).Systemic absorption from the patch must be considered in patientsreceiving oral class 1 antiarrhythmic drugs (eg, mexiletinehydrochloride).

    Treatment with the 5% lidocaine patch consists of the applicationof no more than 3 patches daily for a maximum of 12 hours, withthe patch applied directly to the area of maximal pain (theFDA-approved dosage for PHN). Titration of the 5% lidocainepatch is not necessary, and an adequate trial would last 2 weeks.

    Opioid Analgesics. Five double-blind randomized trials of oralopioid analgesics have been published since 1998. In patientswith PHN, controlled-release oxycodone hydrochloride titratedto a maximum dosage of 60 mg/d significantly relieved pain,disability, and allodynia compared with placebo.42 In patientswith PDN, controlled-release oxycodone titrated to a maximumdosage of 120 mg/d significantly improved pain, the performanceof daily activities, and sleep compared with placebo; the averagedosage of oxycodone in that trial was 37 mg/d (range, 10-99mg/d).43 Controlled-release morphine sulfate titrated to a maximumdosage of 300 mg/d was superior to placebo in patients withphantom limb pain.44

    In a unique 3-period crossover study comparing treatment withopioid analgesics, TCAs, and placebo in patients with PHN, controlled-releasemorphine sulfate titrated to a maximum dosage of 240 mg/d providedstatistically significant benefits for pain and sleep but notfor physical function and mood.45 In that trial, patients preferredtreatment with opioid analgesics compared with TCAs and placebodespite a greater incidence of adverse effects and more dropoutsduring opioid treatment. In a double-blind randomized studythat compared 2 different dosages of levorphanol tartrate inpatients with a variety of peripheral and central neuropathicpain syndromes, patients receiving the higher dosage reportedsignificantly greater pain reduction, but there were no differencesbetween groups in mood, sleep, or interference with daily activities.46In that study, patients with central poststroke pain were theleast likely to report improvement; only 30% with this disordercompleted the trial. Notably, measures of cognitive functionwere administered in 2 of these studies, and it was reportedthat treatment with opioid analgesics did not impair performance.45-46Considered together, the results of these 5 studies providea reliable base of evidence for considering opioid analgesicsto be a first-line treatment for neuropathic pain.

    The most common adverse effects of opioid analgesics are constipation,sedation, and nausea; these effects most likely contributedto the relatively high withdrawal rates found in the placebo-controlledtrials. In elderly patients treated with opioid analgesics,cognitive impairment and problems with mobility can occur, whichmay contribute to an increased risk of hip fracture. Most patientsbecome tolerant to these adverse effects, although constipationoften persists. Regular laxative therapy or switching to transdermalfentanyl citrate may help reduce constipation. Opioid analgesicsmust be used cautiously in patients with a history of substanceabuse or attempted suicide, and accidental death or suicidecan occur with overdose. Although patients treated with opioidanalgesics may develop analgesic tolerance (ie, a reductionin analgesic benefit with time), in responsive patients a stabledosage can usually be achieved. All patients taking opioid analgesicsdevelop physical dependence (withdrawal symptoms with abruptdiscontinuation of the drug or rapid dose reduction) and mustbe advised not to abruptly discontinue their medication.

    The risk that substance abuse, a maladaptive pattern of substanceuse leading to clinically significant impairment or distress,will develop in patients with neuropathic pain who do not havea history of substance abuse is unknown but probably low. Opioidabuse must be distinguished from the appropriate desire to continuetaking medication that effectively relieves pain and from apprehensionabout not having adequate access to medications that are oftendifficult to obtain. There is a substantial risk in prescribingopioids to patients with a history of substance abuse; doingso requires very close monitoring. Concerns about causing asubstance abuse disorder when there is no history of one donot justify refraining from using opioid analgesics in patientswith chronic neuropathic pain.

    Numerous short- and long-acting opioid analgesics are available.We hold diverse opinions regarding the algorithm for administeringopioids for neuropathic pain. One approach recommended by manyof us is to begin treatment with opioid analgesics using a short-actingmedication at dosages equianalgesic to the oral administrationof morphine sulfate at 5 to 15 mg every 4 hours as needed. Commonlyused short-acting opioid analgesics include oxycodone aloneand hydrocodone bitartrate and oxycodone in combination withacetaminophen, aspirin, or ibuprofen (a morphine elixir canbe used with patients who have difficulty swallowing).

    After 1 to 2 weeks of treatment, the patient’s total daily dosageof a short-acting opioid analgesic can be converted to an equianalgesicdaily dosage of one of the long-acting opioid analgesics suchas controlled-release morphine, controlled-release oxycodone,transdermal fentanyl, levorphanol, or methadone hydrochloride.Limited access to short-acting medication for breakthrough painmay be appropriate. Conversion of the patient’s treatment regimenfrom short-acting to long-acting medication may require considerabledosage adjustment for 1 to 2 weeks. Once the patient is receivinga stable dosage of a long-acting medication, an adequate trialof an opioid analgesic requires 4 to 6 weeks to assess bothpain and function. Pain reduction without improvement in functionindicates a need to consider modifying treatment. With carefultitration and monitoring, there is no clear maximum dosage ofopioid analgesics. However, evaluation by a pain specialistmay be considered when morphine sulfate equianalgesic dosagesexceeding 120 to 180 mg/d are contemplated. The benefits oflevels higher than 180 mg/d in patients with neuropathic painhave not been established in double-blind trials.

    Careful documentation and appropriate monitoring of treatmentare important for the safe and effective use of opioid analgesics.Model guidelines for the use of controlled substances for thetreatment of pain have been adopted by the Federation of StateMedical Boards of the United States, and the US Drug EnforcementAdministration has recognized that the use of opioid analgesicsis appropriate for treating chronic pain.

    Tramadol. Tramadol is a norepinephrine and serotonin reuptakeinhibitor with a major metabolite that is a µ opioid agonist.There are 2 published double-blind, placebo-controlled randomizedclinical trials of tramadol for neuropathic pain, 1 in patientswith PDN and 1 in patients with painful polyneuropathy of variouscauses, including PDN.47-48 In both trials, tramadol hydrochloridetitrated to a maximum dosage of 400 mg/d significantly relievedpain compared with placebo. Beneficial effects of tramadol treatmenton allodynia48 and quality of life47were also reported.

    The adverse effects of tramadol include dizziness, nausea, constipation,somnolence, and orthostatic hypotension. These occur more frequentlywhen the dosage is escalated rapidly and with concurrent administrationof other drugs that have similar adverse-effect profiles. Thereis an increased risk of seizures in patients treated with tramadolwho have a history of seizures or who are also receiving antidepressants,opioids, neuroleptics, or other drugs that can reduce the seizurethreshold. Serotonin syndrome may occur if tramadol is usedconcurrently with other serotonergic medications, especiallyselective serotonin reuptake inhibitors (SSRIs) and monoamineoxidase inhibitors. Tramadol may cause or exacerbate cognitiveimpairment in elderly patients, and dosage adjustment is necessaryin patients with renal or hepatic disease. Abuse of tramadolis considered rare but has been observed.

    To decrease the likelihood of adverse effects and increase patientadherence to treatment, tramadol should be initiated at lowdosages—50 mg once or twice daily—and then titratedevery 3 to 7 days by 50 to 100 mg/d in divided doses as tolerated.The maximum dosage of tramadol hydrochloride is 100 mg 4 timesdaily (in patients older than 75 years, 300 mg/d in divideddoses), and an adequate trial requires 4 weeks.

    Tricyclic Antidepressants. The first medication category thatproved effective for neuropathic pain in placebo-controlledtrials was TCAs.25-28 Although clinical trials of patients withHIV sensory neuropathy,49-50 pain from spinal cord injury,51and cisplatin-induced neuropathy52 found little benefit of treatmentwith amitriptyline hydrochloride when compared with placebo,an apt summary of the overall efficacy of TCAs in neuropathicpain is provided by the title of a review by Max.53

    The primary problem with the use of TCAs is their adverse-effectprofile; TCAs must be used cautiously in patients with a historyof cardiovascular disease, glaucoma, urinary retention, or autonomicneuropathy. Almost 20% of patients treated with nortriptylineafter a myocardial infarction developed adverse cardiac eventsin a recent study.54 Consequently, a screening electrocardiogramto check for cardiac conduction abnormalities is recommendedbefore beginning treatment with TCAs, especially in patientsolder than 40 years. As with opioid analgesics, TCAs must beused cautiously when there is a risk of suicide or accidentaldeath from overdose. They may block the effects of certain antihypertensivedrugs (eg, clonidine or guanethidine), and they interact withdrugs metabolized by cytochrome P4502D6 (eg, cimetidine, phenothiazines,and class 1C antiarrhythmics). All SSRIs inhibit cytochromeP4502D6, and to prevent toxic concentrations of TCAs in theplasma, caution must be exercised in the concomitant administrationof TCAs and SSRIs and when switching from one drug class tothe other. In elderly patients, TCAs may cause balance problemsand cognitive impairment. Milder adverse effects of TCAs includesedation, anticholinergic effects (eg, dry mouth or constipation),postural hypotension, and weight gain.

    Although most clinical trials of TCAs for neuropathic pain haveexamined amitriptyline, this drug is not recommended in elderlypatients because of the risk of significant adverse events.Nortriptyline and desipramine hydrochloride have fewer adverseeffects and are generally better tolerated than amitriptyline.In a recent randomized double-blind trial, nortriptyline wasfound to provide equivalent analgesic benefits in patients withPHN when directly compared with amitriptyline but was bettertolerated.55

    Patients must understand that TCAs have an analgesic effectthat has been demonstrated to be independent of their antidepressanteffect. To decrease adverse effects and increase patient adherenceto treatment, TCAs should be initiated at low dosages—10to 25 mg in a single dose at bedtime—and then titratedevery 3 to 7 days by 10 to 25 mg/d as tolerated. Although theanalgesic effect of TCAs has been thought to occur at lowerdosages than the antidepressant effect, there is no systematicevidence of this. However, some data are consistent with a dose-responserelationship; TCAs should be titrated to dosages of 75 to 150mg/d as tolerated. If a blood level of approximately 100 ng/mLof the active drug and its metabolite is not found at dosagesof 100 to 150 mg, titration can be continued further with caution.Blood levels of 500 ng/mL or higher of the active drug and itsmetabolite are associated with toxicity, and for titration higherthan 100 to 150 mg/d, blood levels should be monitored and anelectrocardiogram performed. An adequate trial of a TCA wouldlast 6 to 8 weeks with at least 1 to 2 weeks at the maximumtolerated dosage.

    Selecting a First-line Medication. Medication acquisition costsvary greatly by geographic region, insurance plan, industryhealth plan contracts, and availability of pharmaceutical companyprograms for patients without drug benefit plans. Physiciansshould become as familiar as possible with the acquisition costsof the medications they prescribe and with the reimbursementsprovided by their patients’ insurance plans. Doing so will notonly benefit the finances of their patients but will also maximizeadherence to treatment recommendations. Consideration shouldbe given to the availability of generic versions of medicationsused in treating chronic neuropathic pain. Tramadol, TCAs, andsome opioid analgesics are available in generic forms with acquisitioncosts considerably lower than the 2 first-line medications thatare still protected by patent: gabapentin and the 5% lidocainepatch.

    Tricyclic antidepressants must be used with extreme cautionin elderly patients because of the risk of toxic adverse effectsto the heart and anticholinergic adverse effects. In addition,gabapentin, opioid analgesics, tramadol, and TCAs must all beused with caution in older patients because of the risk of fallsand cognitive impairment.

    Tricyclic antidepressants have numerous contraindications, especiallyin patients with cardiovascular disease, because of the risksof conduction defects, arrhythmias, tachycardia, stroke, andacute myocardial infarction. In patients with renal insufficiency,the dosage of gabapentin or tramadol must be adjusted; in patientswith hepatic disease, dosage adjustment of tramadol is necessary.Opioid analgesics must be used with caution in patients witha history of substance abuse.

    Tricyclic antidepressants may be especially useful for treatingdepression in patients with chronic pain, but the risk of intentionaloverdose must be kept in mind; there is a much higher risk ofsuicide with TCAs compared with other antidepressants. In addition,many patients with chronic pain have disturbed sleep, and trialsof gabapentin and TCAs have demonstrated improvements in thisarea.

    Many patients with neuropathic pain also have nonneuropathicpain (eg, osteoarthritis), and opioid analgesics and tramadolhave demonstrated efficacy in the treatment of both types. Ithas been suggested that TCAs should be used in treating constantpain and that carbamazepine-like anticonvulsants should be usedfor lancinating pain. However, the results of the randomizedcontrolled trials of TCAs and anticonvulsants that have systematicallyassessed pain quality show no evidence of a differential treatmentresponse.

    Onset of pain relief is faster with the 5% lidocaine patch,opioid analgesics, and tramadol than with gabapentin or TCAs.This is primarily because gabapentin and TCAs require slowertitration to effective dosages owing to their adverse effects.Gabapentin, the 5% lidocaine patch, and opioid analgesics allhave fewer adverse drug interactions than tramadol or TCAs.

    Sequential and Combination Treatment With First-line Medications.The percentage of patients with neuropathic pain who do notrespond to 1 of these 5 first-line medications but who thenobtain satisfactory pain relief from a different one is unknown.Even within a class of medication, some patients fail to respondto one medication but then respond to another. In a crossovertrial comparing amitriptyline and nortriptyline in 31 patientswith PHN, 5 patients had moderate or severe pain when administerednortriptyline but none or mild pain with amitriptyline, and4 patients had the opposite pattern of response.55 Current understandingof the pathophysiologic mechanisms of neuropathic pain is consistentwith the existence of multiple pain mechanisms, each of whichmay respond differently to medications with different mechanismsof action.13-16 Therefore, there is both an empiric and theoreticalbasis for recommending that patients who do not respond to 1of these 5 first-line medications be treated with another one.

    It is common for patients to have a partial response to thesemedications, and combination treatment should be consideredwhen this occurs. No studies have systematically examined theefficacy of various possible combinations of these 5 medicationscompared with monotherapy. Despite the lack of controlled data,combinations of 2 or more of these first-line medications canbe recommended when patients have a partial response to a singleone or at the beginning of treatment, either to increase thelikelihood of a beneficial response or when a medication thatrequires titration to reach an effective dosage is also beingused. Disadvantages of combination therapy include an increasedrisk of adverse effects as the number of medications is increasedand difficulty identifying which of several medications is responsiblefor the adverse effects.

    Second-line Medications. When patients do not have a satisfactoryresponse to treatment with the 5 first-line medications aloneor in combination, several medications can be considered second-line.Because these second-line treatments are used less often byphysicians and fewer trials have examined their efficacy, theiruse is not described in detail. Recommendations for second-linemedications are based on positive results from a single randomizedcontrolled trial or inconsistent results from multiple randomizedcontrolled trials, with 1 exception.

    Other Anticonvulsant Medications. Lamotrigine is the 1 second-linepharmacologic treatment for which there is evidence of efficacybased on consistent results of multiple randomized controlledtrials for HIV sensory neuropathy,56-57 PDN,58 and central poststrokepain59 as well as in a subgroup of patients with incompletespinal cord lesions in a trial of patients with pain from spinalcord injury.60 We do not consider lamotrigine a first-line treatmentfor neuropathic pain because of the slow and careful titrationrequired and the risk of both severe rash and Stevens-Johnsonsyndrome associated with its use.

    Carbamazepine has a well-established beneficial effect for trigeminalneuralgia24, 30 and is approved by the FDA for the treatmentof this neuropathic pain syndrome. In patients with PDN, someevidence exists for a beneficial effect of carbamazepine, butresults from studies of phenytoin are inconsistent; these clinicaltrials were conducted more than 20 years ago and do not meetcurrent methodological standards.24, 26-28 On the basis of clinicaltrials of anticonvulsants for chronic neuropathic pain, lamotrigineand carbamazepine can be recommended for patients who have notresponded to an adequate trial of gabapentin when treatmentwith an anticonvulsant is sought.

    Evaluation of the role of other second-generation anticonvulsants(eg, levetiracetam, oxcarbazepine, tiagabine, topiramate, andzonisamide) for the treatment of neuropathic pain must awaitpublication of the results of randomized placebo-controlledtrials. Although several anticonvulsant medications block sodiumchannels, available anticonvulsants have different and oftenmultiple mechanisms. Therefore, nonresponse to 1 anticonvulsantdoes not necessarily predict nonresponse to the category asa whole.

    Other Antidepressant Medications. Selective serotonin reuptakeinhibitors have fewer adverse effects and are generally bettertolerated than TCAs. In studies of patients with PDN, paroxetineand citalopram were associated with statistically significantlygreater pain relief than placebo, whereas fluoxetine hydrochloridewas found to be no more effective than placebo.25-28 Sustained-releasebupropion hydrochloride was studied in a controlled trial ofpatients with different peripheral and central neuropathic painsyndromes and found to provide statistically significant painrelief compared with placebo.61 In a recent randomized, 3-periodcrossover trial of venlafaxine hydrochloride and imipraminehydrochloride in patients with painful polyneuropathy, bothantidepressants demonstrated superior pain relief compared withplacebo but did not differ from each other.62 A placebo-controlledcrossover trial of 13 patients with chronic neuropathic painfollowing breast cancer surgery failed to find a significantbenefit of venlafaxine vs placebo for the primary end point(daily pain diary ratings) but did find greater relief associatedwith venlafaxine treatment for 2 secondary pain end points.63Results of these clinical trials indicate that bupropion, citalopram,paroxetine, and venlafaxine can be recommended for patientswho have not responded to an adequate trial of nortriptyline(or another TCA) when additional treatment with an antidepressantis being considered.

    Beyond Second-line Medications. Other medications sometimesused for the treatment of patients with neuropathic pain includecapsaicin, clonidine, dextromethorphan, and mexiletine. Accordingto our clinical experience and the inconsistent results of clinicaltrials, these medications may occasionally be effective in individualcircumstances.

    Future Needs

    Treatment duration in most clinical trials of neuropathic painhas typically been 8 weeks or less; therefore, durability ofpain relief and the long-term safety and tolerability of treatmentare unknown. With chronic disorders, it is important to considerthe long-term cost-effectiveness of treatment.64 Although thedevelopment of new treatments for neuropathic pain is continuingrapidly,65-66 few clinical trials have directly compared medicationoptions.45, 55, 62 Such comparisons will make it possible todetermine not only whether treatments vary in their efficacy,safety, and tolerability but also, when conducted in the samepatients, the extent to which treatment response with one medicationpredicts response to others.45 Systematic evaluation of combinationtreatment is needed as well. Although a large percentage ofpatients with neuropathic pain are currently treated with 2or more of the first- and second-line medications discussed,little is known about which patients are most likely to benefitfrom combination treatment and whether such treatment has additiveor synergistic effects. Morever, because combinations of pharmacologicand nonpharmacologic treatments have received little study inpatients with neuropathic pain, it is unknown, for example,whether physical therapy or psychological treatment providesan additional benefit beyond that obtained from pharmacologictreatment alone.


    CONCLUSIONS

     Jump to Section
     • Top
     • Introduction
     • Diagnosis and assessment
     • Pathophysiologic mechanisms
     • Treatment recommendations
     • Conclusions
     • Author information
     • References


    Interest in the mechanisms and treatment of chronic neuropathicpain has increased during the past several years, and this islikely to result in significant treatment advances in the future.These advances will make it possible to go beyond the determinationof whether treatment is effective to the identification of whattreatments are most effective for which patients.13, 67 Progressin basic science will lead to a greater understanding of thepathophysiologic mechanisms of neuropathic pain. Important goalsfor clinical research are to devise methods for reliably identifyingspecific mechanisms in individual patients and to target treatmentto them.13-17 Greater attention should also be paid to developingpreventive interventions for patients who are at risk for chronicneuropathic pain, including patients undergoing breast cancersurgery,68 those with herpes zoster,69 and those with diabetes.70


    AUTHOR INFORMATION

     Jump to Section
     • Top
     • Introduction
     • Diagnosis and assessment
     • Pathophysiologic mechanisms
     • Treatment recommendations
     • Conclusions
     • Author information
     • References


    Corresponding author and reprints: Robert H. Dworkin, PhD, Departmentof Anesthesiology, University of Rochester School of Medicineand Dentistry, 601 Elmwood Ave, Box 604, Rochester, NY 14642(e-mail: robert_dworkin@urmc.rochester.edu ).

    Accepted for publication July 24, 2003.

    Author contributions: Study concept and design (Drs Dworkin,Backonja, Rowbotham, Allen, Argoff, Bushnell, Farrar, Galer,Haythornthwaite, Hewitt, Loeser, Schmader, Stein, Thompson,Turk, Watkins, and Weinstein); acquisition of data (Drs Dworkin,Rowbotham, Argoff, Bushnell, Max, and Saltarelli); analysisand interpretation of data (Drs Dworkin, Rowbotham, Allen, Argoff,Bennett, Farrar, Galer, Hewitt, Loeser, Max, Saltarelli, Stein,Wallace, and Weinstein); drafting of the manuscript (Drs Dworkin,Backonja, Rowbotham, Argoff, Bennett, Haythornthwaite, Hewitt,Max, Schmader, Stein, and Weinstein); critical revision of themanuscript for important intellectual content (Drs Dworkin,Backonja, Rowbotham, Allen, Argoff, Bennett, Bushnell, Farrar,Galer, Hewitt, Loeser, Max, Saltarelli, Schmader, Stein, Thompson,Turk, Wallace, Watkins, and Weinstein); statistical expertise(Drs Dworkin, Bennett, Farrar, and Thompson); obtained funding(Drs Dworkin and Galer); administrative, technical, and materialsupport (Drs Dworkin, Schmader, and Turk); study supervision(Dr Dworkin).

    Dr Dworkin has received research support, consulting fees, orspeakers bureau honoraria in the past year from Abbott Laboratories,Allergan, AstraZeneca, Bristol-Myers Squibb, Elan Pharmaceuticals,Eli Lilly and Co, Endo Pharmaceuticals, King Pharmaceuticals,Johnson and Johnson, NeurogesX, Novartis Pharmaceuticals, Ortho-McNeilPharmaceutical, Pfizer, Purdue Pharma, Quigley Pharma, ReliantPharmaceuticals, and UCB Pharma. Dr Rowbotham has been affiliatedwith or had financial involvement with Abbott Laboratories,Allergan, Bayer, Biogen, Blue Shield/United Behavioral Health,Elan, Endo Pharmaceuticals, Fulcrum Pharma, GrünenthalGMBH, Hind Health Care, Lineberry Research Associates, NeuroMedTechnologies, Ortho-McNeil/Johnson and Johnson PharmaceuticalResearch Institute, Pain Management Research LLC/Teikoku PharmaUSA, Pfizer, Schwarz Biosciences, and WinPharm Associates. DrFarrar has received research or grant support from Pfizer, Cephalon,Smithkline Beecham, Knoll, and Searle; served as a consultantfor Abbott Laboratories, Alza, Endo Pharmaceuticals, UCB Pharma,and Faulding; and served on the speakers bureau of Purdue Frederick.Dr Galer has been an employee of and has stock options in EndoPharmaceuticals and has received royalty payments from HindHealth Care. Dr Max has participated in ongoing scientific collaborationsor relevant discussions with Johnson and Johnson, Purdue Pharma,and Merck; has had employment conversations with Abbott Laboratories;and has served as a paid consultant for Pfizer, Abbott Laboratories,Endo Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, EliLilly, Bayer, Elan, Novartis, Watson Laboratories, and Wyeth-Ayerst.

    Endo Pharmaceuticals provided an unrestricted educational grantto the University of

  17. Online pharmacies, Internet pharmacies, or Mail Order Pharmacies are pharmacies that operate over the Internet and send the orders to customers. Online or internet pharmacies might include:

    • Pharmacy benefit manager – A large administrator of corporate prescription drug plans
    • Legitimate internet pharmacy in the same country as the person ordering.
    • Legitimate internet pharmacy in a different country than the person ordering. This pharmacy usually is licensed by its home country and follows those regulations, not those of the international orders.
    • Illegal or unethical internet pharmacy. The web page for an illegal pharmacy may contain lies about its home country, procedures, or certifications. The “pharmacy” may send outdated (expired shelf life ) or counterfeit medications and may not follow normal procedural
  18. Rochester Office of Professional Education(Rochester, NY) to support a meeting on the treatment of neuropathicpain, and all authors except for Dr Max received an honorariumfor participation in the meeting from the University of Rochester.

    We thank William H. Bayer, MD, Kenneth R. Epstein, MD, RonaldM. Epstein, MD, Joseph M. Kovaz, MD, Bill H. McCarberg, MD,Gerald G. Ryan, MD, Thomas R. Taylor, MD, PhD, and Philip S.Whitecar, MD, for their thoughtful reviews of an initial draftof this article; Paul Lambiase and Mary Gleichauf of the Universityof Rochester Office of Professional Education for invaluablesupport; and Lili Dworkin for assistance with manuscript preparation.

    From the Department of Anesthesiology, University of Rochester, Rochester, NY (Dr Dworkin); Department of Neurology, University of Wisconsin, Madison (Dr Backonja); Department of Neurology, University of California, San Francisco (Dr Rowbotham); AstraZeneca, Wilmington, Del (Dr Allen); Department of Neurology, North Shore University Hospital, Manhasset, NY (Dr Argoff); Department of Anesthesiology, McGill University, Montreal, Quebec (Drs Bennett and Bushnell); Department of Neurology, University of Pennsylvania, Philadelphia (Dr Farrar); Endo Pharmaceuticals, Chadds Ford, Pa (Dr Galer); Department of Psychiatry, Johns Hopkins University, Baltimore, Md (Dr Haythornthwaite); Ortho-McNeil Pharmaceutical, Raritan, NJ (Dr Hewitt); Departments of Neurosurgery (Dr Loeser) and Anesthesiology (Dr Turk), University of Washington, Seattle; Pain and Neurosensory Mechanisms Branch, National Institute of Dental and Craniofacial Research, Department of Health and Human Services, Bethesda, Md (Dr Max); Pfizer, Groton, Conn (Dr Saltarelli); Department of Medicine and Geriatric Research, Education, and Clinical Center, Duke University and Durham VA Medical Centers, Durham, NC (Dr Schmader); Department of Anesthesiology, Freie Universität Berlin, Berlin, Germany (Dr Stein); Innovus Research Inc, Medford, Mass (Dr Thompson); Department of Anesthesiology, University of California, San Diego (Dr Wallace); Department of Psychology, University of Colorado, Boulder (Dr Watkins); and Department of Anesthesiology, University of Utah, Salt Lake City (Dr Weinstein).

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