• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Antidepressants
• Anticonvulsants
• Systemic local anesthetics
• Topical Analgesics
• Miscellaneous Drugs
• N-methyl-D-Aspartate Receptor Blockers
• Opioid Analgesics

   In recent years, varieties of adjunct analgesics have been used to treat chronic pain syndromes, including NSAIDs, antidepressants, anticonvulsants, local anesthetics, topical agents, baclofen, and N-methyl-D-aspartate (NMDA) receptor antagonists. Tricyclic antidepressants and anticonvulsants have been used as the first-line drugs in the treatment of neuropathic pain. If a patient does not respond to treatment with different agents within one drug class, agents from a second drug class may be added. When all first-line options have been exhausted, narcotic analgesics may provide some benefit, with the risks of tolerance and addiction (1).

   The main advantage of the selective serotonin reuptake inhibitors is the favorable side-effect profile. However, selective serotonin reuptake inhibitors are clearly less effective than tricyclic antidepressants NNT (Number Needed to Treat to reach 50% pain relief): 6.7 vs. 2.4)(7). Venlafaxine is a selective serotonin/noradrenaline reuptake inhibitor. Randomized controlled trials show good pain relief for painful polyneuropathy and also for neuropathic pain following treatment of breast cancer. Duloxetine(8), a newer selective serotonin/noradrenaline reuptake inhibitor, has also been demonstrated to have some analgesic effects in neuropathic pain. Bupropion, a noradrenergic compound, also has analgesic effects in neuropathic pain and often is activating. The latter effect can be particularly helpful in the hypoactive, depressed, sedated, or fatigued patients. However, bupropion(9) is not significantly better than the placebo in the treatment of patients with non-neuropathic chronic low back pain. Trazodone (a serotonin-reuptake inhibitor as well as a postsynaptic serotonin receptor antagonist) does not appear to be effective for the treatment of chronic pain. Evidence for the efficacy of trazodone in treating insomnia is also very limited. Table 2 lists tricyclic antidepressants commonly used for pain management.

   Valproic acid has been proven to be effective in reducing the frequency of migraine attacks. Recent randomized double-blind placebo-controlled trials found that valproates may provide significant pain relief in patients of post-herpetic neuralgia (10) and diabetic neuropathy. However, negative results have also been reported. Common side effects include tremor, ankle swelling, sedation, and gastrointestinal discomfort. Weight gain and hair loss may be a major cosmetic concern especially for younger patients. Valproates should not be used for children less than 2 years of age because of hepatotoxicity. Generally, valproates are not the first line choice for neuropathic pain.

   In the last decade, gabapentin has gained popularity for the treatment of neuropathic pain. The analgesic efficacy of gabapentin has been demonstrated in several types of nonmalignant neuropathic pain. It is now used to treat a wide variety of pain conditions. Due to the high safety profile, few drug-drug interactions, and the proven analgesic effect in several types of neuropathic pain, gabapentin is now recommended as a first-line co-analgesic for the treatment of a variety of neuropathic pains, especially in the medically ill and elderly patients. The most common adverse effects are drowsiness, dizziness, and unsteadiness. Gabapentin should be started at a dose of 100–300 mg at bedtime. If titrated carefully, gabapentin is usually well tolerated up to 3600mg daily. However, gabapentin has a nonlinear pharmacokinetic profile. The rate of bioavailability decreases, as the dose increases.

   Pregabalin is a GABA analog with similar structure and actions to gabapentin. It has antiepileptic, analgesic and anxiolytic activity. Pregabalin is indicated for the management of neuropathic pain associated with diabetic neuropathy(11) and post-herpetic neuralgia(12). Food does not significantly affect the extent of absorption. Pregabalin is not protein-bound and exhibits a plasma half-life of about 6 hours. Hepatic metabolism is negligible, and most of the oral dose (95%) appears unchanged in the urine. At a dose of 300mg/day, about 45% of diabetic neuropathy patients had 50% pain relief. This means that pregabalin has a NNT of 2.2 for diabetic neuropathy. Pregabalin seems to be more effective than gabapentin and other anticonvulsants for neuropathic pain. Common side effects of pregabalin include dizziness, sedation, dry mouth and peripheral edema (13).

   Oxcarbazepine is a keto-derivative of carbamazepine with better tolerability. It can block sodium-dependent action potentials. The medication does not induce hepatic enzymes and has less drug-drug interaction than carbamazepine. Recent studies have reported oxcarbazepine to be promising for refractory diabetic neuropathic pain with a NNT of 6.0 (14). Another randomized trial in diabetic neuropathy has shown that patients taking oxcarbazepine 1,200 and 1,800 mg/day had improvements in pain compared with the placebo. However, the results were not statistically significant.

   Lamotrigine is an antiepileptic drug that stabilizes neural membranes by blocking the activation of voltage-sensitive sodium channels and inhibiting the presynaptic release of glutamate. Lamotrigine has also been reported to relieve nonmalignant neuropathic pain in several randomized trials (15). A recent controlled three year prospective open study also found lamotrigine to be highly effective in reducing migraine aura and migraine attacks (16). For adults, lamotrigine has to be started in a low dose such as 25 mg twice a day and slowly increased in 6-8 weeks to the target dose. The most serious adverse effect of lamotrigine is skin rash, which is dose-dependent and more common in combination with valproate. Other adverse effects include headaches, tremors, nausea, drowsiness, dizziness, and an unsteady gait.

   Topiramate has been reported to be effective in reducing migraine frequency (17). However, double-blind clinical controlled studies do not find topiramate to be significantly more effective than the placebo in reducing pain scores in patients with painful diabetic polyneuropathy (18). Topiramate treatment may reduce chronic sciatica in some patients but causes frequent side effects that cause patients to cease taking the drug. The mechanisms of action include blockade of sodium channels, enhancement of GABA inhibition, and attenuation of kainate-induced responses at glutamate receptors. The starting dose is usually small, e.g., 25 mg twice a day for an adult. It may be increased weekly by 50 mg with an increment to 200 mg per day. Topiramate may induce memory loss, word-finding difficulties, disorientation, and sedation. The other common adverse affects are renal calculi, tremors, dizziness, ataxia, headaches, fatigue, and gastrointestinal upset. Topiramate may also induce significant weight loss. This medication may be more helpful in obese pain patients.

   Tiagabine is a selective gamma-aminobutyric acid reuptake inhibitor. A recent open label study indicates that tiagabine might reduce pain intensity and improve sleep in patients with neuropathic pain(19). Zonisamide also has been used to treat neuropathic pain. However, a recent randomized, controlled pilot trial on zonisamide for diabetic neuropathic pain failed to yield statistical significance between the zonisamide and the placebo group(20). Levetiracetam has the advantage of not interacting with food or other drugs. Some anecdotal evidence suggests that levetiracetam could be effective in the treatment of neuropathic pain (21). More studies are needed to evaluate the clinical efficacy and safety of these antiepileptics for the treatment of pain.

   Capsaicin is the spicy ingredient in chili pepper. It can deplete substance P from the terminals of afferent C-fibers, potentially leading to decreased pain perception. Capsaicin creams are effective in reducing post surgical pain in cancer patients. When applied topically, it may initially release substance P and cause severe burning pain. The pain related to the use of capsaicin gradually decreases over a few days, if the cream is applied regularly. A lower concentration cream (0.025%) or the application of a topical local anesthetic may help some patients decrease the initial burning pain, and tolerate the medication better. It is important to warn patients not to get any trace of the cream on mucous membranes since this causes severe pain.

   Opioids are classified according to the activity on the opioid receptors as full agonists, partial agonists or mixed agonists-antagonists. Commonly used full agonists include hydrocodone, codeine, morphine, oxycodone, hydromorphone, methadone, and fentanyl. Buprenorphine is a partial agonist. It has lower intrinsic efficacy compared to other full opioid agonists, and displays a ceiling effect to analgesia. Mixed agonist-antagonists include pentazocine, butorphanol tartrate, dezocine and nalbuphine hydrochloride. These mediations block opioid analgesia at one type of receptor (mu) while simultaneously activating other opioid receptors (kappa). Mixed agonist-antagonists should not be used together with full agonists because they may cause withdrawal syndrome and increased pain.

   Narcotics are also classified as mild to strong according to their potency. Codeine is the prototype of the mild opioid analgesics. The duration of action (2–4 hours) is similar to that of aspirin and acetaminophen. It is commonly used together with NSAIDs, when NSAIDs alone have proven ineffective. Hydrocodone, oxycodone, propoxyphene, and meperidine are other mild opioid analgesics. Meperidine is likely to cause dysphoria, or less commonly to cause myoclonus, encephalopathy, and seizures. These toxic effects result from metabolites, such as normeperidine, that accumulates with repeated doses. Meperidine should be avoided in patients who require chronic treatment. Morphine and hydromorphone are the prototypes of high-potency opioid analgesics. Morphine has a relatively rapid onset, especially when administered parenterally, and a short duration of action, about 2–4 hours. Sustained-release oral preparations (MSContin and Kadian with duration of action 12 hours and 24 hours respectively) are useful for patients requiring chronic opioid therapy.

   Route of administration is important to consider when choosing opioids. Oral administration of opioids is the preferred route, because it is the most convenient and cost-effective. Oral opioids are available in tablet, capsule and liquid forms and in immediate, and controlled-release, formulations. Patients should be informed not to break the controlled-release tablets since this can cause it to become the immediately released and cause a potential overdose. If patients cannot take medication orally, other less invasive routes such as transdermal or rectal routes should be tried. Intramuscular administration of narcotics should be avoided because this route is often painful and inconvenient, and absorption is not reliable. Intravenous administration may be more expensive and is not practical for most chronic pain patients.

   The advantage of transdermal administration is it bypasses gastrointestinal absorption. Fentanyl is currently the only opioid commercially available for transdermal administration. Fentanyl patches come in four sizes, delivering medication at 25, 50, 75 and 100 mcg per hour. Each patch contains a 72-hour supply of fentanyl passively absorbed through the skin during this period. Plasma levels rise slowly over 12 to 18 hours after the patch placement. The dosage form has an elimination half-life of 21 hours. Unlike intravenous fentanyl, transdermal administration of fentanyl is not suitable for rapid dose titration. It is often used for patients with chronic pain and already on opioids. As with other long acting analgesics, all patients should be provided with oral or parenteral short acting opioids for breakthrough pain.

   Intrathecal analgesia may be considered when pain cannot be controlled by oral, transdermal, subcutaneous, or intravenous routes because side effects such as confusion and nausea further limit dose titration. Documentation of the failure of maximal doses of opioids and adjunct analgesics administered through other routes should precede consideration of intrathecal analgesia. For patients with chronic pain, who have failed or cannot tolerate other treatment modalities, before implantation of permanent pump a trial is usually needed of single intrathecal injections, epidural injection or continuous epidural administration. If there is significant pain relief without major side effects during the trial, the patient may be a candidate for permanent implantation of an intrathecal delivery system. Morphine is the most commonly used intrathecal drug used for pain relief. The main indication of the long-term intrathecal opioids is intractable pain in the lower part of the body. With proper selection and screening, good to excellent pain relief is expected in up to 90 percent of patients.

   Physicians need to be familiar with side effects of opioids before prescribing these medications. Common side effects of opioids include constipation, sedation, nausea, vomiting and respiratory depression due to overdoses. Occasionally, opioids may cause myoclonus, seizures, hallucinations, confusion, sexual dysfunction, sleep disturbances and pruritus. Constipation is a common problem associated with opioid administration. Tolerance to the constipating effects of opioids hardly ever occurs during the chronic therapy. Some patients are too embarrassed to tell the physician about constipation problems, and physicians should always ask patients about this. Mild constipation can usually managed by an increase in fiber consumption and the use of mild laxatives such as milk of magnesia. Severe constipation may be treated with a stimulating cathartic drug, (e.g., bisacodyl, standardized senna concentrate add Myralax and similar drugs).

   Transitory sedation is common if opioid doses are increased substantially, but tolerance also usually develops rapidly. Reducing the opioid dose, switching to another opioid, or use of CNS stimulants such caffeine, dextroamphetamine or methylphenidate may help increase alertness. Nausea and vomiting may be managed with antiemetics chosen according to the modes of action. These antiemetics include metoclopramide, chlorpromazine, haloperidol, scopolamine, and hydroxyzine. Patients receiving long-term opioid therapy usually develop tolerance to the respiratory-depressant effects of these agents. However, respiratory depression often occurs due to an overdose, or when pain is abruptly relieved and the sedative effect of the opioids is no longer opposed by the stimulating effect of pain. To reverse respiratory depression, opioid antagonists (e.g., naloxone) should be given incrementally in doses that improve respiratory function, but do not reverse analgesia to avoid reoccurrence of severe pain.

   Accumulation of normeperidine, a metabolite of meperidine, may cause seizures, especially in patients with chronic renal insufficiency. Therefore, meperidine is only indicated for acute use. Chronic use of meperidine should be avoided. Tramadol is a synthetic narcotic. It is most commonly used for mild pain. Tramadol may decrease the seizure threshold and induce seizures. This medication should be avoided in patients with a history of seizures. It should not be not be used with tricyclic antidepressants. The recommended maximum dosage of tramadol is less than 400mg/day.

   Tolerance and physical dependence should be expected with long-term opioid treatment and not confused with psychological dependence or drug abuse, which is characterized by compulsive use of narcotics. Patients may crave for narcotics and continue to consume it despite physiological or social damages due to the abuse of narcotics. Tolerance of opioids may be defined as the need to increase dosage requirements over a period of time to maintain optimum pain relief. For most pain patients the first indication of tolerance is a decrease in the duration of analgesia for a specific dose. Patients with stable disease do not usually require increasing doses. Increasing the dosage requirement is most consistently correlated with a progressive disease that produces more intense pain. Physical dependence on opioids is revealed when opioids are abruptly discontinued, or when naloxone is administered and is typically manifested as anxiety, irritability, chills and hot flashes, joint pain, lacrimation, rhinorrhea, diaphoresis, nausea, vomiting, abdominal cramps and diarrhea. The mildest form of the opioid abstinence syndrome may be manifested as viral “flu-like” syndromes. For short acting opioids (i.e., codeine, hydrocodone, morphine, hydromorphone), the onset of withdrawal symptoms may occur within 6 to 12 hours and peak at 12 to 72 hours after discontinuation. For opioids with long half-lives (i.e., methadone and transdermal fentanyl) the onset of the withdrawal syndrome may be delayed for 24 hours or more after drug discontinuation. If a rapid decrease or a discontinuation of opioids is possible because the pain has been effectively eliminated, the opioid abstinence syndrome may be avoided by withdrawal of the opioid on a schedule that provides half the prior daily dose for each of the first 2 days and then reduces the daily dose by 25% every 2 days thereafter, until the total dose (in morphine equivalent) is 30 mg/day. The drug may be discontinued after 2 days on 30mg/day dose according to 1992 guidelines from the American Pain Society. Transdermal clonidine (0.1 to 0.2 mg/day) may reduce anxiety, tachycardia and other autonomic symptoms associated with opioid withdrawal.

   Diminishing opioid analgesic efficacy and increased pain during the course of opioid therapy is quite common. It is traditionally considered as a result of opioid tolerance. However, this could also be the result of opioid-induced hyperalgesia. It has been demonstrated that pain sensitivity to experimental pain stimulation such as cold pressure is increased in low back pain patients after one month of morphine therapy. It is now believed that opioid-induced hyperalgesia is related to changes in the central nervous system including descending facilitation, up-regulation of spinal dynorphin, and enhanced evoked release of excitatory transmitters from primary afferents(26). Clinically, it is difficult to distinguish opioid tolerance and opioid-induced hyperalgesia. However, the issue of opioid-induced pain sensitivity should also be considered when an adjustment of opioid doses is being contemplated because the opioid treatment is failing to provide the expected analgesic effects and/or there is an unexplainable pain exacerbation following a period of an effective opioid treatment. With opioid-induced hyperalgesia an increased opioid dose is not always the answer. Less opioid may be more effective in pain reduction in some cases. This approach may also be accompanied with an opioid rotation and/or adding additional non-opioid adjunctive medications. In addition, basic science studies have suggested that combined use of opioids and clinically available NMDA receptor antagonists may prevent or reduce the development of both pharmacological tolerance and opioid-induced pain sensitivity(27).