Role of Anti-depressants and Anti-
epileptics in chronic pain
management

• Chronic and acute pain are different.
• Require different treatment approaches.
• Acute pain is a protective response to
injury.
• Chronic pain may be a maladaptive
response.
• Acute pain most often is nociceptive.
• Chronic pain may be nociceptive or
neuropathic (i.e., resulting from neuronal
maintenance of pain either peripherally or
in the central nervous system).
• Nociceptive pain usually is treated with
anti-inflammatory or analgesic medications.
• Neuropathic pain typically is treated with
medications that influence
neurotransmitters
Background

Peripheral neuropathic pain Central neuropathic pain Non-neuropathic pain*
Complex regional pain syndrome Multiple sclerosis Arthritis
Human immunodeficiency virus sensory neuropathy Myelopathies Inflammatory arthritis
Idiopathic peripheral neuropathy Parkinson's disease Osteoarthritis
Infection Poststroke pain Chronic low back pain
Metabolic disorders Chronic neck pain
Alcohol and other toxins Fibromyalgia
Diabetic neuropathy Post-traumatic pain
Nutritional deficiencies
Nerve compression or entrapment
Phantom limb pain

The Special Interest Group on Neuropathic Pain (NeuPSIG) proposal:
Tricyclic antidepressants (TCAs), Gabapentinoids, and selective serotonin–
norepinephrine reuptake inhibitors (SNRI) as the first-line drugs for
neuropathic pain.
Lidocaine, Capsaicin, and Tramadol as the second-line treatment.
Strong opioids (Morphine and Oxycodone) and botulinum toxin-A (BTX-A) as
third-line treatments for neuropathic pain.

Tricyclic Anti-depressants

The Special Interest Group on Neuropathic Pain (NeuPSIG) proposal:
Tricyclic antidepressants (TCAs), Gabapentinoids, and selective serotonin–
norepinephrine reuptake inhibitors (SNRI) as the first-line drugs for
neuropathic pain.
Lidocaine, Capsaicin, and Tramadol as the second-line treatment.
Strong opioids (Morphine and Oxycodone) and botulinum toxin-A (BTX-A) as
third-line treatments for neuropathic pain.

Independent analgesic action
Pain relief in depressed and non-depressed patients with chronic pain
Secondary and Tertiary amines.
Desipramine, amitriptyline and its metabolite, nortriptyline, and imipramine.

Amitriptyline can act as a local anesthetic by blocking voltage-gated sodium
channels.
Antidepressants may have additional mechanisms of action by modulating
the immune system, which is heavily involved in neuropathic pain.
TCAs may directly interfere with central sensitization by blocking NMDA
receptors in the spinal cord .

"Dirty drugs” that affect multiple targets.
Anticholinergic effects are a major concern because of the risk of
cardiotoxicity, limiting the dosage to less than 100 mg/day.
Also include dry mouth, orthostatic hypotension, constipation, and urinary retention.
In order to overcome these problems, selective SNRIs, in particular duloxetine, have
been introduced in the treatment of neuropathic pain.

Duloxetine has shown consistent efficacy in painful diabetic neuropathy and
low back pain.
Dosing of duloxetine is simple with 60 mg once or twice daily appearing to be
equally effective.
Nausea is the most common adverse effect of duloxetine, which appears to
be reduced by lowering the dosage to 30 mg once daily for 1 week before
increasing to 60 mg once daily.

Anti-epileptics.

Pregabalin and gabapentin are both derived from GABA, but they have no
effect on the GABAergic system.
Their mechanism of action includes binding to the alpha-2/delta-1 subunit
of the voltage-gated calcium channels in several areas of the central
nervous system (CNS) and spinal cord in which these channels are
expressed.
This explain their analgesic, anxiolytic, and anticonvulsant
pharmacological properties.
Brainstem structures, from which descending modulatory fibers originate,
may be a key target of the analgesic action of gabapentinoids, because
alpha-2/delta-1 expression is very high in these areas.

Pregabalin has greater binding affinity for the alpha-2/delta-1 subunit.
Analgesic potency in neuropathic pain is six times higher compared with
gabapentin.
The system-L protein family [L-type amino acid transporters (LAT)] enables
the transport of large neutral amino acids, including phenylalanine, leucine,
isoleucine, and valine; intestinal absorption of gabapentin and pregabalin is
also facilitated by this protein family.
Results from preclinical studies suggest that gabapentin is transported
exclusively by the LAT1 transporter.
This results in dose-limited absorption, which may be due to saturation of the
facilitated transport process. An additional pathway also appears to mediate
the absorption of pregabalin, resulting in a high level of absorption into the
bloodstream

Both drugs do not undergo metabolism by phase I or phase II enzymes and
are excreted unmodified by the kidneys.
Not prone to pharmacokinetic drug–drug interactions and, specifically, are not
substrates of the cytochrome P450 (CYP) system, which is involved in the
metabolism of many other drugs.
This is of significant clinical value, because the two drugs can be safely used
in comorbid patients on pharmacological polytherapy. Gabapentin and
pregabalin can be safely used in combination with other analgesic drugs used
in the treatment of neuropathic pain.

Pregabalin and gabapentin are well tolerated drugs.
The most commonly reported adverse effect of...... pregabalin is
dizziness, followed by somnolence, dry mouth, edema, and blurred vision,
with treatment discontinuation due to somnolence occurring in 4% of patients.
For....... gabapentin, dizziness and somnolence occur in more than 20%
of patients and are the most commonly reported adverse effects; other
adverse effects include confusion and peripheral edema.
For both drugs, adverse effects are dose-dependent and reversible.

Gabapentin and pregabalin may be initiated in the emergency department but
the onset of pain relief is not typically seen immediately.
These agents require a slow titration to effect over several weeks.
As a result, they should be started at a low dose and titrated based upon
clinical effect.
Additionally, neither gabapentin nor pregabalin should be administered with
opioids as both may potentiate the euphoric effects of opioids when taken
concomitantly, increasing susceptibility to abuse and a worsening respiratory
and CNS depression.

Dosing/Titration/Therapeutic switch of Pregabalin
Dosing in diabetic peripheral neuropathy
Begin at 50 mg PO three times daily and increase to 100 mg three times daily
within 1 week based on efficacy and tolerability.
Dosing in postherpetic neuralgia
Begin at 75 mg PO twice a day or 50 mg three times daily and increase to
100mg three times daily within 1 week based on efficacy and tolerability.
Dosing may be further escalated over 2–4 weeks to a maximum of 300 mg
twice a day, or 200 mg three times daily.
Converting to Pregabalin: Gabapentin should be discontinued over a
minimum of 1 week before starting pregabalin at a dose of 50 mg three times
daily.

Treatment Strategy

Use of a pain scale facilitates clinical evaluation of the patient's response to a
therapeutic drug trial.
An assessment of quality of life and activities of daily living should be
incorporated into the clinical evaluation of the therapeutic drug trial.
Identification of psychiatric comorbidity may suggest the use of an
antidepressant for nonpain indications.

Neuropathic pain
A tricyclic antidepressant is the preferred initial therapy if the patient has
coexisting insomnia, anxiety, or depression. (cost effective also)
An antiepileptic drug (e.g., gabapentin is preferred if the patient cannot
tolerate the side effects of tricyclic antidepressants, has cardiac
contraindications to the use of tricyclic antidepressants (e.g., conduction
abnormalities, recent cardiac event), or is a “frail elder.”
Titrate the selected medication to achieve clinical effect or to the maximum
tolerated dosage.
With gabapentin, if no effect is seen at a dosage of 1,800 mg per day,
discontinue the drug; if a partial effect occurs, titrate the drug to a dosage
of 2,400 to 3,600 mg per day.
Monitor response to treatment.

If monotherapy is tolerated but only partially effective, combine an antidepressant
with an antiepileptic drug.
If monotherapy is poorly tolerated or ineffective, choose a first-line agent from a
different medication class or use a second-line agent.
If pain relief remains inadequate, consider use of a short-acting or long-acting opioid
or tramadol.

Non-neuropathic pain
Exercise is the primary therapy for chronic low back pain and fibromyalgia.
Begin treatment of low back pain with a nonsteroidal anti-inflammatory drug (not
effective in the treatment of fibromyalgia).
Consider use of a tricyclic antidepressant as a pain adjuvant to promote sleep and
alleviate muscle spasm.
In appropriately selected patients, consider use of a short- or long-acting opioid or
tramadol.
Empiric use of antiepileptic drugs such as gabapentin is not justified by the current
literature but is common practice in pain clinics.

Conclusion
The pharmacotherapy of neuropathic pain is challenging and for many
patients effective treatment is lacking.
Neuropathic pain is also associated with interference with sleep, depression,
and anxiety that, if not properly treated, will negatively influence the
responses to analgesic drugs.
When choosing a drug, consider comorbidity, prioritizing the use of those
drugs that can satisfy more than one medical need, as for instance
gabapentinoids in the case of interference of pain with sleep, or SNRI in the
case of associated depression.

Consider patients comorbidities taking are at higher risk of drug–drug
interactions that may be responsible for adverse drug reactions or therapeutic
failure.
Since a large number of drug–drug interactions involve metabolism by the
CYP enzymes, drugs which do not undergo metabolism by CYP or do not
undergo liver metabolism at all, as in the case of gabapentinoids, are
preferable to other drugs.
This holds true in the case of combination pharmacotherapy, in which two or
more analgesic drugs are co-administered when one is not enough, a
therapeutic strategy that seems to have evident advantages.

Thanks......