Pain is “a sensory and emotional unpleasant experience associated with, or described in the form of, actual or potential tissue damage” (International Association for the Study of Pain, IASP). There are two types of pain, and two types of pain, one is injury-receptive pain, caused by direct noxious stimuli, a key component of the body’s defense mechanisms, associated with tissue injury or inflammation, also known as inflammatory pain; the other is neuropathic pain, due to peripheral or central nervous system injury, associated with abnormal tactile and thermo-sensory responses outside the area of injury, including a range of pain syndromes, such as complex regional pain syndrome, phantom limb pain, cancer pain, AIDS pain, trigeminal neuralgia, and postherpetic neuralgia.
There are many treatment options for neuropathic pain (NPP), including neuromodulation and neurodesis, but medications remain the primary treatment. Currently commonly used therapeutic drugs include gabapentin, pregabalin, tricyclic antidepressants, 5% lidocaine patches, tramadol, and opioids. This article will be classified to introduce the currently used drugs and some drug advances.
I. Antidepressants.
1. Tricyclic Antidepressants (TCAs)
TCAs are widely used in the treatment of various NPPs, including trigeminal neuralgia, peripheral neuralgia in diabetic patients, and postherpetic neuralgia, but there is evidence that they are ineffective in HIV-associated pain. NMDA receptors to inhibit neuronal hyperexcitability.
Amitriptyline and promethazine are the most widely used drugs in TCAs, which are metabolized in the liver after absorption to the active products: desmethyl amitriptyline and desmethyl promethazine, respectively.
2.Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are different from traditional TCAs in that they can selectively inhibit 5-HT reuptake without affecting norepinephrine, but it is because of this high selectivity that the analgesic effect of SSRIs is not as obvious as that of TCAs, which supports the view that non-selective inhibitors of 5-HT and norepinephrine have better analgesic effect than selective inhibitors. Such drugs include sertraline, paroxetine, fluoxetine, and escitalopram.
SSRIs have fewer side effects than TCAs, including anxiety, insomnia, headache, drowsiness, and sexual dysfunction, and can be used as an alternative to TCAs. In addition, these drugs have a risk of liver toxicity, and liver function should be checked during the first 3 months of treatment.
II. Antiepileptic drugs.
Since NPP is accompanied by epilepsy, which is characterized by hyperexcitability of neurons, antiepileptic drugs can effectively treat NPP because they have the property of inhibiting neuronal hyperexcitability. the main mechanisms of antiepileptic drugs for NPP are: reducing the inward flow of neuronal Na+ and Ca2+, directly and indirectly enhancing the inhibitory effect of GABA, by depleting the storage of neurotransmitter glutamate or blocking the site of action of glutamate NMDA receptors to reduce the activity of the excitatory neurotransmitter glutamate. Antiepileptic drugs can inhibit neuronal hyperexcitability through one or more mechanisms.
Numerous articles have reported that gabapentin (gabapentine) can treat a variety of NPP. gabapentin has good bioavailability and a good safety profile, is not deformed in vivo, and there is no concern about interdrug reactions or effects on liver enzymes. However, it is expensive and can be replaced with amitriptyline for patients for whom price is a primary consideration.
Pregabalin, a lipophilic GABA analogue with the same binding site as gabapentin, was approved by the FDA in September 2004 for the treatment of diabetic peripheral neuropathy and post-vesicular neuralgia with an average effective pain relief time of 3 days, while improving sleep, mood disturbances and health-related quality of life.
Phenytoin sodium (phenytoin sodium) inhibits neuronal hyperexcitability by blocking the rapid Na+ inward flow necessary to form action potentials. Some studies have demonstrated that phenytoin sodium is most effective in mild to moderate NPP. New applications have recently been discovered, such as intravenous use may be effective in acute attacks of chronic NPP, and some refractory cases can be relieved with 15 mg/kg IV over 2 hours.
Carbamazepine (Carbamazepine) inhibits neuronal hyperexcitability by blocking Na+ channels and voltage-dependent Ca2+ and is effective in diabetic neuropathy, postherpetic neuralgia and spinal tuberculosis pain. Caution should be exercised when increasing the dose or combining with other drugs, as there are many reports in the literature that carbamazepine can affect drug metabolism by reducing various hepatic cytochrome enzymes P450, which may lead to many unpredictable interdrug reactions. Oxcarbazepine is structurally similar to carbamazepine, has reduced side effects on liver enzymes, and may be used as an alternative to carbamazepine.
Lamotrigine is used to treat NPP by blocking Na+ channels and inhibiting the release of the excitatory neurotransmitter glutamate. Its efficacy is dose-dependent, with limited efficacy below 300 mg/d, and becomes highly effective above 300 mg/d. However, lamotrigine is highly individualized and must be started at low doses and increased slowly to avoid the dose-dependent side effect of skin rash.
Topiramate (Topiramate) is a new anticonvulsant with a mechanism of action that may be similar to that of phenytoin sodium in blocking Na+ inward flow and may also directly or indirectly enhance the inhibitory effect of the neurotransmitter GABA. 42 patients were treated with topiramate in a randomized double-blind controlled trial by Khoromi et al. 29 of them completed the trial with doses ranging from 25 to 800 mg/d (mean 200 mg/d), with a mean pain relief of 19%. This trial showed that although topiramate may reduce sciatica, it is not recommended due to the high incidence of side effects and the frequency of patients dropping out of the study, unless there is a better therapeutic index.
III. Topical therapeutic agents.
Topical treatment has many advantages, such as less interaction with other drugs, less systemic side effects, and no titration of drug dose.
The 5% lidocaine patch is FDA approved for the treatment of post-herpetic neuralgia. It is also effective for persistent pain and abnormal pain in patients with non-postherpetic neuralgia, with the latter being more effective.
Ketamine0 is an MNDA receptor antagonist used to treat chronic pain, but oral administration is limited due to side effects. Topical application of ketamine gel significantly reduced mechanical hyperalgesia induced by capsaicin, and no significant local or systemic side effects were observed.
The mechanism of action of capsaicin is unknown, but it is currently thought to desensitize afferent sensory nerves by inhibiting the release and depletion of a neurotransmitter known to sense injury, called substance P. Capsicin can moderate chronic skeletal muscle or pathological pain, but is less efficient and can be used as an adjunctive therapeutic agent.
IV. Opioids.
A growing body of literature supports opioids and analgesics for the treatment of chronic pain, with side effects maintained in a tolerable state. Morphine has a strong analgesic effect and is more effective in combination with other drugs, and can be considered for patients who are ineffective with other drugs. The effect of opioids in the treatment of NPP is comparable to that of antidepressants and antiepileptic drugs, but the long-term application of opioids is still controversial due to drug resistance and addiction.
V. Non-steroidal anti-inflammatory drugs (NASIDs).
NASIDs can be used to treat inflammation, pain and fever, and the mechanism of action is to block prostaglandin synthesis by inhibiting the precursor enzyme COX. Generally NASIDs are effective for skeletal muscle pain and various other conditions, such as arthritis, dysmenorrhea and headache, at their respective recommended doses for NPP, but some patients do better with specific NSAIDs. The literature contradicts whether NASIDs are effective for long-term treatment, but combined with other drugs is effective for chronic pain, so it can be used as an adjunct to combined other drugs [2].
VI. Other drugs.
Dextromethorphan, an NMDA receptor antagonist, is effective in diabetic peripheral neuropathy. Some trials have shown that high-dose dextromethorphan (270 mg/d) is also effective in traumatic NPP, but the effect is highly variable from patient to patient, and those with fast metabolism seem to be more effective than those with slow metabolism.
Mexiletine, a commonly used antiarrhythmic drug, blocks Na+ channels to inhibit neuronal hyperexcitability in the treatment of NPP. Tremont [12] et al. studied by meta-analysis that mexiletine (600 mg/d) was similar to morphine, gabapentin, amitriptyline and amantadine in the treatment of NPP, superior to placebo, and had longer-lasting effects in peripheral pain (trauma and diabetes) and central pain with longer lasting effects.
VII. Combination therapy.
Foreign literature reports that about 70% of patients are effective for a single therapy, and the remaining 30% do not have enough pain relief, in which case a combination of drugs is needed. Some patients are clinically effective for a certain treatment, but may be limited due to dose-related side effects, for such patients can be used in combination to relieve pain without worrying about dose-related side effects. However, there is very little information on the use of combination drugs, drug selection is entirely empirical, and drug selection is guided by therapeutic efficacy without regard to side effects.
There is better evidence that gabapentin combined with venlafaxine or morphine may be effective in refractory NPP where conventional treatment has failed. Gabapentin combined with morphine dose-dependently inhibited dorsal horn neuronal responses in rats with ligated spinal nerves, and this inhibition was stronger than morphine or gabapentin alone. This suggests that the combination of morphine and gabapentin is successful because both the excitatory and inhibitory effects of morphine and gabapentin on the nervous system are stimulated, and the low doses of both drugs reduce the side effects of each.
Although the combination therapy can improve the therapeutic effect and reduce the adverse effects, it needs to be used from the lowest dose and titrated to observe the effect. In addition, some problems may occur with the combination therapy, such as interdrug reactions, complicated dose and increased risk, which need to be clarified by further research.
In conclusion: Although research on NPP has been increasing in recent years, treatment is still a major problem, often facing the embarrassment of ineffective treatment or poor results, which brings great pain to patients and seriously affects their normal work and daily life. This article focuses on the commonly used drugs and some new drug advances. With the emergence of new drugs, the therapeutic effects and adverse drug reactions of NPP have improved compared with the previous ones, but they are still not ideal, and drug combination therapy, although some studies have confirmed better effects, still faces many problems that need further in-depth research. Clinicians can choose different drugs and methods according to the patient’s specific situation to achieve the best treatment effect.
Improving the therapeutic effect of NPP and improving the quality of life of patients is an inevitable trend in medical development and requires the unremitting efforts of clinicians and researchers.