top of page

Adjuvant Drugs for Chronic Pain- Dr. Debjyoti Dutta, MD,FIPP

Classification of Drugs

Classification of Drugs

Adjuvant Drugs for Chronic Pain

Anti Convulsant Drugs -


A Multifaceted Pharmacological Profile


Carbamazepine, chemically akin to imipramine, emerged in the 1960s as a remedy for trigeminal neuralgia. Its pharmacological mechanisms bear resemblance to phenytoin, primarily manifesting in the prolongation of the inactivated state of sodium channels. Notably, Carbamazepine yields therapeutic outcomes akin to lithium, contributing to its efficacy in various conditions. Additionally, it exhibits antidiuretic properties, likely attributed to its facilitation of antidiuretic hormone (ADH) action on renal tubules. The multifarious pharmacological attributes of Carbamazepine underscore its significance in the treatment landscape.

Carbamazepine Dose

Pharmacokinetics of Carbamazepine: Insights into Absorption, Binding, Metabolism, and Half-life Dynamics

Carbamazepine undergoes intricate pharmacokinetic processes, starting with oral absorption characterized by slow and variable rates, largely attributed to its poor water solubility. Once absorbed, approximately 75% of Carbamazepine binds to plasma proteins. Within the liver, it undergoes metabolism through oxidation to active metabolites like 10-11 Epoxy Carbamazepine, hydroxylation, and conjugation to inactive forms. Notably, Carbamazepine acts as both a substrate and an inducer for hepatic enzymes, particularly CYP3A4 and CYP2C9. Initially, its plasma half-life ranges from 20 to 40 hours, but with chronic medication, it decreases to 10-20 hours due to autoinduction of metabolism. These pharmacokinetic attributes illuminate the complexities underlying Carbamazepine's therapeutic profile and its modulation within the body.

Adverse Effects of Carbamazepine: Comprehensive Overview

Carbamazepine, while efficacious in treating various conditions, carries a spectrum of adverse effects. Dose-related neurotoxicity presents as sedation, dizziness, vertigo, and diplopia, often worsening with higher doses, leading to vomiting, diarrhoea, and aggravated seizures. Acute intoxication may result in coma, convulsions, and cardiovascular collapse. Hypersensitivity reactions encompass rashes, photosensitivity, hepatitis, lupus-like syndrome, and rarely, agranulocytosis, aplastic anaemia, and Stevens-Johnson syndrome (SJS). Common leukopenia is attributed to hypersensitivity, while elderly individuals are prone to water retention and hyponatremia. Additionally, Carbamazepine increases the risk of minor foetal malformations, necessitating cautious management and monitoring of adverse effects during its use.

Utilization in Pain Management:

Carbamazepine finds distinct indications in pain management. It serves as a first-line treatment for Trigeminal Neuralgia, demonstrating efficacy in alleviating associated discomfort. In cases of Diabetic Neuropathy, Carbamazepine is considered as a therapeutic option in select instances, offering relief from neuropathic symptoms. Additionally, it may be employed in managing Post-herpetic neuralgia, although its use is contingent upon specific clinical considerations. Beyond its labeled indications, Carbamazepine is utilized off-label in addressing Peripheral Neuropathy and Central Neuropathic Pain, reflecting its potential utility in a broader spectrum of neuropathic conditions where conventional treatments may be inadequate. Such versatile applications underscore the importance of individualized approaches to pain management and the role of Carbamazepine in diversifying therapeutic options.


Oxcarbazepine emerges as a contemporary counterpart to Carbamazepine, offering distinctive pharmacological characteristics. It swiftly transforms into an active metabolite, which subsequently undergoes glucuronide conjugation but not oxidation, setting it apart from its precursor. Notably, Oxcarbazepine circumvents the toxic effects linked with the epoxide metabolite of Carbamazepine, enhancing its safety profile and tolerability. These attributes position Oxcarbazepine as a promising alternative in the management of various neurological disorders, presenting a refined approach to therapeutic intervention while mitigating potential adverse effects associated with its predecessor.

Oxcarbazepine: Considerations on Drug Interactions and Autoinduction

In the realm of drug interactions and autoinduction, Oxcarbazepine presents a distinct profile compared to Carbamazepine. Notably, it exhibits fewer marked drug interactions and displays a diminished propensity for autoinducing metabolism in comparison to its predecessor. Its weak enzyme inducer property further contributes to its favorable interaction profile, offering clinicians a therapeutic option with reduced potential for pharmacokinetic complications. These attributes highlight Oxcarbazepine as a pharmacologically refined agent, offering improved safety and predictability in clinical practice while managing various neurological conditions.

Oxcarbazepine Safety Profile: Hepatotoxicity and Hyponatremia Considerations

When evaluating the safety profile of Oxcarbazepine, distinct characteristics emerge in comparison to Carbamazepine. Notably, Oxcarbazepine presents a lower risk of hepatotoxicity, offering a favourable attribute in terms of hepatic safety compared to its counterpart. However, it is important to note that Oxcarbazepine carries a higher risk of hyponatremia when juxtaposed with Carbamazepine. These contrasting safety profiles underscore the importance of individualized risk assessment and vigilant monitoring during the administration of Oxcarbazepine, particularly regarding hepatic function and serum sodium levels, ensuring optimal patient management and safety throughout the course of treatment.

Oxcarbazepine Indications and Tolerance: Enhanced Therapeutic Profile

Oxcarbazepine shares similar indications with Carbamazepine, encompassing a spectrum of neurological conditions where anticonvulsant therapy is warranted. However, it distinguishes itself by potentially offering superior tolerability in comparison. Despite its comparable therapeutic indications, Oxcarbazepine demonstrates a better toleration profile, which may enhance patient compliance and minimize adverse effects. Notably, its dose-to-dose potency is approximately one and a half times less than Carbamazepine, indicating a nuanced dosing consideration for optimal therapeutic outcomes. These characteristics position Oxcarbazepine as a promising alternative in the management of neurological disorders, presenting an improved balance between efficacy and tolerability in clinical practice.


Gabapentin: Understanding its Mechanism of Action

Gabapentin, a lipophilic derivative of GABA, operates by enhancing GABA release without directly engaging as an agonist at GABAA receptors. Within neuropathic pain conditions, both Gabapentin and pregabalin elicit a specific analgesic effect by modulating neuronal voltage-sensitive Ca2+ channels, specifically those containing alpha 2 delta 1 subunits. This modulation effectively reduces the influx of Ca2+ into presynaptic neurons, thereby potentially decreasing glutamate release and neuronal excitability. However, the precise mechanism underpinning the anticonvulsant and analgesic effects remains uncertain. It's debated whether the modulation of alpha 2 delta 1 subunits or the enhancement of GABA neurotransmission predominantly contributes to the therapeutic actions of Gabapentin and pregabalin. Further research is necessary to elucidate the intricacies of their pharmacological mechanisms.

Gabapentin in Clinical Practice: Usage, Pharmacokinetics, Interactions, and Dosage

Gabapentin serves as the first-line medication for managing neuralgic pain linked to diabetic neuropathy and postherpetic neuralgia. Its oral absorption is efficient, and it is primarily excreted unchanged in urine, boasting a relatively short half-life of approximately 6 hours. Notably, Gabapentin exhibits minimal drug interactions, making it a favorable choice for combination therapy. Moreover, no adjustments are typically necessary in the dosage of primary antiepileptic drugs when introducing Gabapentin into the treatment regimen. The recommended dosage regimen typically entails initiating therapy with 300 mg once daily, with the option to escalate to 300–600 mg thrice daily as needed for optimal pain control. These aspects collectively underscore Gabapentin's clinical versatility, favourable pharmacokinetic profile, and straightforward dosing protocol in various neuropathic pain conditions.

Precautions and Considerations for Gabapentin Initiation

Before initiating Gabapentin treatment, it is imperative to evaluate renal and thyroid function due to its potential impacts on these systems. Hyperthyroidism should be monitored for, necessitating careful assessment before treatment commencement. Dosing should be initiated cautiously, titrated slowly based on individual response and tolerability, particularly in patients with renal impairment where dose reduction may be required. For instance, a weekly increment of 300 mg could be considered. Additionally, patients should be assessed for suitability before starting treatment, given Gabapentin's potential for abuse and dependence. These precautions emphasize the importance of thorough evaluation and monitoring before embarking on Gabapentin therapy to ensure patient safety and optimize treatment outcomes.

Gabapentin: Adverse Effects

Typical side effects of Gabapentin encompass mild sedation, while other common occurrences may involve feelings of tiredness, dizziness, and unsteadiness.


Pregabalin: Contemporary Counterpart to Gabapentin

Pregabalin emerges as a modern congener of Gabapentin, exhibiting comparable pharmacodynamic and pharmacokinetic attributes to its predecessor. Notably, both drugs share similar properties in terms of their mechanisms of action and metabolic pathways. Clinical indications for Pregabalin largely overlap with those of Gabapentin, reflecting their shared utility in managing various neurological conditions. This alignment underscores the nuanced yet complementary roles that Pregabalin and Gabapentin play in the therapeutic landscape, offering clinicians options with similar efficacies for addressing neuropathic pain and related disorders.

Pregabalin: Clinical Application in Neuropathic Pain Management

Pregabalin finds widespread application in managing various neuropathic pain conditions, including diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome (CRPS), and other chronic pain types. Its therapeutic scope extends to addressing the diverse etiologies and manifestations of neuropathic pain, offering relief and improving quality of life for individuals grappling with these debilitating conditions. The versatility of Pregabalin underscores its significance as a valuable therapeutic option in the comprehensive management of neuropathic pain syndromes, providing clinicians with an effective tool to address the complexities of chronic pain management.

Pregabalin Dosage: Dose: 75-150 mg BD, max 600 mg/day

Pregabalin: Profile of Adverse Effects

Pregabalin is reputed to have a less conspicuous sedative impact when contrasted with gabapentin. However, potential side effects associated with its usage may encompass impaired concentration, rashes, peripheral edema, and weight gain. Despite its purported reduced sedative properties, Pregabalin may still induce various adverse reactions, emphasizing the necessity for vigilant monitoring and individualized management strategies to mitigate these effects and optimize treatment outcomes.

Comparison of Gabapentin and Pregabalin

When considering the pharmacokinetics of Pregabalin, it exhibits linear and predictable behaviour, with absorption unaffected by food and displaying less variability between patients compared to Gabapentin. Moreover, its bioavailability is notably higher and more consistent than Gabapentin. Mechanistically, Pregabalin binds to central nervous system calcium channels and demonstrates a more potent reduction in excitatory neurotransmitter release compared to Gabapentin. Clinically, Pregabalin is approved for treating fibromyalgia and generalized anxiety disorder (GAD), distinguishing its therapeutic scope from that of Gabapentin. These distinctions in pharmacokinetics, mechanisms of action, and clinical applications highlight the nuanced differences between Pregabalin and Gabapentin, offering clinicians varied options for addressing neurological and psychiatric conditions effectively.

Categories of Antidepressant Medications

Antidepressant medications encompass various categories tailored to address different aspects of depression and related disorders. Selective Serotonin Reuptake Inhibitors (SSRIs) such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline are widely used for their selective action on serotonin reuptake. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) including desvenlafaxine, duloxetine, venlafaxine, milnacipran, and levomilnacipran offer dual inhibition of serotonin and norepinephrine reuptake. Atypical antidepressants like bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine provide unique mechanisms of action, targeting various neurotransmitter systems. Tricyclic Antidepressants (TCAs) such as amitriptyline, doxepin, imipramine, nortriptyline, and desipramine exert their effects through serotonin and norepinephrine reuptake inhibition, sodium channel blockade, and NMDA antagonism. Monoamine Oxidase Inhibitors (MAOIs) like the selegiline patch and tranylcypromine are less commonly used due to dietary restrictions and potential side effects. Each category offers distinct pharmacological profiles and considerations, enabling healthcare providers to tailor treatment regimens to individual patient needs effectively.


Dosage and Titration Guidelines - Initiating treatment with Amitriptyline follows a cautious "Start Low, Go Slow" approach to minimize adverse effects. Typically, therapy begins with a low 10mg dose at night, adjusting the dosage based on individual response and tolerability. Dosage increments can occur gradually, with a maximum nighttime dosage capped at 100mg. However, benefits are observed to plateau beyond 50mg, while side effects may increase. Special considerations apply to concurrent medications, especially if the patient is on other antidepressants, warranting a lower initial dose of 25mg. Incremental adjustments of 10mg per week are advised, with potential for dose reduction to 5mg increments if over-sedation becomes problematic. These structured guidelines aim to optimize therapeutic efficacy while minimizing the risk of adverse reactions, allowing for individualized treatment approaches tailored to patient needs and tolerability levels.

Amitriptyline: Precautions, Contraindications, and Withdrawal Protocol

When considering the use of Amitriptyline, several precautions and contraindications merit attention. Patients with arrhythmias or those in the immediate post-myocardial infarction recovery phase should avoid its usage. Additionally, caution is warranted in specific populations including elderly individuals, those with glaucoma, prostatic hypertrophy, or cardiovascular disease. Safety measures extend to patients engaged in activities requiring focus and coordination, particularly during treatment initiation and after dosage adjustments. In cases where Amitriptyline proves ineffective after 4-6 weeks, withdrawal should be gradual, reducing the dosage by 10mg weekly intervals. These comprehensive protocols and considerations aim to ensure patient safety, minimize adverse effects, and optimize therapeutic outcomes when utilizing Amitriptyline in clinical practice.

Risk of Serotonin Syndrome with Co-Prescribing: Awareness and Symptoms

The co-prescribing of medications such as Tramadol, Tricyclic Antidepressants, Duloxetine, and SSRIs elevates the risk of serotonin syndrome, a severe drug reaction stemming from excessive serotonin levels in the body. Serotonin syndrome manifests through symptoms like agitation, confusion, rapid heart rate, high blood pressure, sweating, tremor, diarrhea, and fever. In severe instances, serotonin syndrome can pose life-threatening risks and necessitate immediate emergency intervention. Awareness of this potential complication and prompt recognition of symptoms are crucial in managing patients receiving combinations of these medications, ensuring timely and appropriate medical attention to mitigate the risks associated with serotonin syndrome.


Dosage and Monitoring Guidelines for Diabetic Neuropathy

The medication is approved for diabetic peripheral neuropathy and osteoarthritis management. The recommended dosage ranges from 60mg to 120mg daily. Initially, patients should begin with 30mg daily for 2 weeks, gradually increasing to a maximum of 120mg daily. If there's an inadequate response after 2 months, discontinuation is advised. Regular patient monitoring, conducted at least every 3 months, is essential to assess treatment efficacy and patient well-being. However, individuals with liver disease are not recommended to use the medication, and it should be avoided in cases of severe renal impairment where creatinine clearance is less than 30 ml/min. Adhering to these guidelines ensures optimal management of diabetic neuropathy while mitigating potential risks associated with the medication.

Adverse Effects of Duloxetine

Duloxetine is associated with a range of adverse effects that patients may experience during treatment. These include common symptoms such as nausea, dry mouth, vomiting, fatigue, insomnia, drowsiness, decreased sexual appetite, sexual dysfunction, weight loss, headache, dizziness or light-headedness, and sweating. Additionally, duloxetine may contribute to more serious adverse effects, such as increased blood pressure and the risk of serotonin syndrome. Awareness of these potential side effects is crucial for both patients and healthcare providers to monitor and manage effectively throughout the course of treatment with duloxetine.


Capsaicin and TRPV1 Activation: Local Sensitization

Capsaicin, acting on the transient receptor potential cation channel subfamily V member 1 (TRPV1), initiates local sensitization processes. Through its activation of TRPV1 receptors, capsaicin induces sensory neuron depolarization, subsequently heightening sensitivity to various stimuli. This heightened sensitivity primarily involves responses to heat, acidosis, and endogenous agonists. By triggering TRPV1 activation, capsaicin sets in motion mechanisms that amplify local sensory responses, contributing to the perception of pain and other sensory experiences. Understanding these processes is integral to elucidating capsaicin's role in sensory modulation and its applications in pain management and related therapies.

Effects of Topical Exposure to Capsaicin

Topical exposure to capsaicin induces a variety of sensations, including heat, burning, stinging, and itching. These sensory experiences are characteristic of capsaicin's interaction with nociceptors. At high concentrations or with repeated use, capsaicin elicits persistent effects on nociceptors, leading to reduced spontaneous activity and a loss of responsiveness to stimuli. This phenomenon underscores capsaicin's capacity to modulate sensory perception and highlights its potential as a therapeutic agent in managing pain and related conditions. Understanding these effects aids in harnessing the therapeutic benefits of capsaicin while minimizing adverse reactions.

Approved Uses and Recommendations for Capsaicin Cream

Capsaicin 0.075% cream is approved for treating painful diabetic neuropathy and post-herpetic neuralgia, offering relief for these neuropathic pain conditions. NICE (National Institute for Health and Care Excellence) recommends its use specifically for localized neuropathic pain when oral treatments are either contraindicated or not well tolerated. However, it's essential to note that capsaicin cream strength varies, with a lower 0.025% concentration primarily indicated for osteoarthritis pain rather than neuropathic pain. Understanding these distinctions helps healthcare providers make informed decisions regarding the appropriate use of capsaicin cream for specific pain management needs, ensuring optimal patient care and treatment outcomes.

Application Guidelines for Capsaicin

Capsaicin is approved for various uses, and its application instructions are straightforward. Patients are advised to apply a pea-sized amount of capsaicin cream to the affected area three or four times daily, ensuring thorough coverage. Additionally, patients should wash their hands immediately after application and avoid using capsaicin on broken or irritated skin to prevent potential irritation. A trial period of at least one month is recommended before assessing efficacy, and if no benefit is observed during this time, discontinuation of use is advised. These guidelines serve as essential considerations for healthcare providers and patients alike, facilitating safe and effective utilization of capsaicin for targeted pain relief and management.



6 views0 comments


bottom of page