Chapter 17
Anticonvulsants in the management of chronic pain

Malin Carmland^1,2, Troels Staehelin Jensen^1,2, & Nanna Brix Finnerup^1,2

¹ Danish Pain Research Center, Aarhus University, Aarhus, Denmark

² Department of Neurology, Aarhus University Hospital, Aarhus, Denmark

Introduction

Anticonvulsants, also called antiepileptic drugs (AED), were primarily introduced for the treatment of epilepsy. Many AEDs have pharmacological actions that can interfere with the processes involved in neuronal hyperexcitability either by decreasing excitatory or increasing inhibitory transmission, thereby exerting a neuronal depressant effect. This may explain why some AEDs are effective in bipolar mood disorders and chronic pain conditions, which may share complex pathophysiological mechanisms manifest in different areas of the nervous system.

Chronic pain is defined as pain that persists or recurs for more than 3 months and can be divided according to etiology [1]. Nociceptive pain, including inflammatory pain, is pain arising from activation of nociceptors, while neuropathic pain is defined as pain arising as pain caused by a lesion or disease of the somatosensory system [2]. A group of pain conditions, which among others include fibromyalgia, temporomandibular disorders and irritable bowel syndrome, do not fall into these two categories of pain. The underlying mechanisms in these pain syndromes are unknown, and in the new ICD‐11 classification, they are classified as primary pain [1]. As reviewed in previous chapters, pharmacotherapy for chronic pain should take place within the context of a multidisciplinary approach that addresses biopsychosocial aspects and begins with a review of active healthful strategies and treatments with the least potential for harm.

This chapter reviews AEDs for the treatment of chronic neuropathic pain, migraine and fibromyalgia.

Antiepileptics in chronic pain: mechanisms of action

Until the beginning of 1990, there were around 7‐8 AEDs on the market. These first‐generation drugs are now accompanied by several second‐ and third‐ generation AEDs. Some have been tested in pain conditions, but far from all. The exact mechanisms by which AEDs relieve chronic pain are not known. Several mechanisms of action may be involved in altering neurotransmission by exerting a neuronal depressant effect in pain pathways [3]. This way, AEDs may attenuate the neuronal hyperexcitability, peripheral and central sensitization and ectopic activity, which are likely the responsible mechanisms underlying chronic pain conditions. These mechanisms of action include modulation of ion channels (sodium, calcium and potassium channels), augmentation of inhibitory effects (particularly by potentiating the inhibitory neurotransmitter gamma‐aminobutyric acid [GABA]) and suppression of abnormal neuronal excitability such as inhibition of glutamate receptors or suppression of neurotransmitter release (Table 17.1).

Table 17.1 Main mechanism of action, common side effects and precautions of commonly used anticonvulsants for chronic pain.

Drug	Main mechanism of action	Side effects and precautions^*
Carbamazepine	Sodium channel blockade	Somnolence, dizziness, ataxia, hyponatremia, leukopenia, nausea, vomiting, dermatological reactions/rash
		Precautions: cardiac insufficiency, previous or current haematological disease, concomitant treatment with anticholinergic medications, risk of suicidal thoughts/behaviour
Oxcarbazepine	Sodium channel blockade	Fatigue, headache, nausea, vomiting, dizziness, somnolence, diplopia, hyponatremia, potential for dermatological and anaphylactic reactions (acute onset) Precautions: Cardiac insufficiency, decreased liver or kidney function, risk of suicidal thoughts/behaviour
Lamotrigine	Sodium channel blockade	Headache, rash, pain, fatigue, diarrhea, nausea, dry mouth, vomiting, irritability, somnolence, dizziness, tremor Precautions: potential dermatologic reactions, risk of suicidal thoughts/behaviour
Lacosamide	Sodium channel blockade	Nausea, headache, dizziness, diplopia Precautions: cardiac rhythm disorders, severe cardiac disease, 2^nd or 3^rd degree AV block is a contraindication, risk of suicidal thoughts/behaviour
Pregabalin	Calcium channel blockade	Headache, somnolence, dizziness Precautions: severe chronic cardiac insufficiency, decreased kidney function (dose reduction), risk of suicidal thoughts/behaviour and abuse
Gabapentin incl. gabapentin ER/enacarbil	Calcium channel blockade (α2δ –unit)	Fever, fatigue, ataxia, dizziness, somnolence, viral infections, sedation, ataxia, dizziness, somnolence Precautions: decreased kidney function (dose reduction), risk of suicidal thoughts/behaviour and abuse
Valproate	Increased GABA inhibition, decreased glutamate excitation, sodium channel blockade	Nausea, tremor Precautions: Potential hepatotoxicity, control haematological parameters
Topiramate	Sodium and calcium channel blockade, increased GABA inhibition, decreased glutamate excitation	Fatigue, weight loss, diarrhoea, nausea, nasopharyngitis, depression, somnolence, paraesthesia, dizziness Precautions: reduced liver function, risk of suicidal thoughts/behaviour
Levetiracetam	Calcium channel blockade (binds to a synaptic vesicle protein SV2A)	Rhinitis, somnolence, headache Precautions: Reduced kidney and liver function (dose reduction)

GABA, γ‐aminobutyric acid. ^*For full list of side effects and precautions, please refer to official summary of product characteristics.

The AEDs carbamazepine (first generation), oxcarbazepine and lamotrigine (both second generation) primarily act by blocking sodium channels. Changes in sodium channels are involved in neuropathic pain conditions [4]. Slowing of the recovery rate of voltage‐gated sodium channels and inhibition of sustained high‐frequency repetitive firing will stabilize membranes and reduce neuronal excitability in the peripheral and central nervous systems. A newer third‐generation AED, lacosamide, enhances the slow inactivation of voltage‐gated sodium channels and inhibits the collapsing response mediator protein 2 (CRMP‐2), which may have a disease modifying role in pain signaling.

Valproate is a first‐generation AED with a wide range of actions including potentiation of GABAergic functions, reduction in excitatory amino acids, sodium channel and glutamate receptor functions, modulation of potassium and calcium homeostasis, and enhancement of serotonergic neurotransmission [3].

Gabapentin and pregabalin are members of second‐generation AEDs. They are structural derivatives of the inhibitory neurotransmitter GABA, but in spite of their name, do not appear to act through the GABAergic neurotransmitter system. The predominant mechanism of action is thought to be through its presynaptic binding to the α₂δ‐1 and 2 subunits of voltage‐gated calcium channels. These are expressed at different levels in the brain, e.g. locus coeruleus and amygdala both involved in nociception and pain processing, as well as in the spinal cord and peripheral nerves. The result is reduced excitatory transmitter release from these tissues, which may explain the anticonvulsant, analgesic and anxiolytic activity [5, 6].