“Illness is the doctor to whom we pay most heed; to kindness, to knowledge, we make promise only; pain we obey.”
– Marcel Proust

The Gabapentinoids

Gabapentin (Neurontin) & Pregabalin (Lyrica)



“Neuropathic” or nerve pain is:

“pain caused by a lesion or a disease of the somatosensory system.”

The somatosensory system is the part of the sensory system concerned with the conscious perception of touch, pressure, pain, temperature, position, movement, and vibration, which arise from the muscles, joints, skin, and fascia.


Central sensitization:

Central Sensitization is a process of hyper-responsiveness to sensory stimuli which is a result of chronic pain-induced changes in the spinal cord and brain. It can be an important contributing process to the chronic pain experience.


It is recommended to first read the following sections to become familiarized with some of the terms and concepts related here:



see also:



Definitions and Terms Related to Pain


Key to Links:

  • Grey text – handout
  • Red text – another page on this website
  • Blue text – Journal publication



Gabapentin (Neurontin) and Pregabalin (Lyrica)

What kind of medicines are gabapentin (Neuroniin) and pregabalin (Lyrica)?

Sometimes referred to as “gabapentenoids,” these two medications carry many labels because of their multiple benefits. Originally used to suppress seizures, these medications are commonly known as anti-epileptics or anti-seizure medications but these terms are misleading and inadequately describe these medications. Perhaps a more accurate description would be “neuromodulators,” medications that modifiy the activity of nerves, nerve pathways or the nervous system.


Both gabapentin and pregabalin are calcium channel blockers while topiramate (Topamax), another neuromodulating drug used in pain management, is a sodium channel blocker. The movement of calcium or sodium through the cell walls of neurons impacts how “excitable” a nerve is and how effectively it transmits messages. By blocking these channels, these drugs make neurons less excitable and reduce the transmission of pain signals, thus reducing both seizure susceptibility but also pain.

How do gabapentin (Neurontin) and pregabalin (Lyrica) differ?


While the FDA has approved these medications for separate indications, most physicians prescribe these medications somewhat interchangeably – if one is ineffective or not tolerated, the other may be advised. There is no firm evidence to answer the obvious questions about which patients should have which drug, and in which order the drugs should be used. Sometimes cost can play a role depending on pharmacy or insurance plan. Sometimes a patient may find one of the two medicines only effective for a particular pain such as sciatica and the other medicine only effective for a different pain such as headaches – so they take both medications (although this is unusual). While both medications offer the same potential side effects, individual patients may experience different side effects with each medication. Overall, pregabalin is characterized by higher potency, quicker absorption rates and greater bioavailability than gabapentin.



The mechanisms of how these two medications work appear to be the same or at least they share significant overlap. In fact, even now, research continues to explore exactly how these medications do work and it is known that different mechanisms
of action are responsible for the different clinical effects and benefits. For those interested in an in-depth exploration of current research into how gabapentinoids work and what these findings imply for choices in chronic pain management, see “Neurobiology of Gabapentin” at the end of this page.


Both gabapentin and pregabalin are excreted essentially unchanged via the kidney and dose adjustments should be make in the presence of impaired kidney function.



However, there are differences between the two. Pregabalin may offer fewer side effects and only pregabalin is FDA approved for fibromyalgia, though most clinicians find gabapentin to be equally effective for fibromyalgia. Gabapentin is believed to be absorbed in a non-linear fashion, meaning the higher the dose, the smaller the percentage of absorption occurs. This is related to possible transporter overload and can be a limiting factor in determining the most effective dosing schedules. However, a study in 2003 indicated that gabapentin maintained a “reasonably” linear manner relative to doses up to 4800 mg per day. In some cases, the use of a time-release formulation of gabapentin can provided superior results with less side effects. Pregabalin is absorbed linearly and is more rapidly and better absorbed (more bioavailable) and is thought to have fewer side effects than gabapentin.


Gabapentin is not a controlled medication that requires a special license for prescribing whereas pregablin is. Medications are given “controlled” status by the FDA when a medication is considered at risk for abuse. When gabapentin was approved by the FDA, gabapentin did not appear to have abuse potential. However, reports are surfacing that both gabapentin and pregabalin are associated with a low incidence of abuse,  particularly in populations of polysubstance and opioid abusers. Both drugs appears to have low addiction potential. Part of the growing concern surrounding the abuse of gabapentin and lyrica is that they may, especially at high doses, contribute to the suppression of the drive to breathe in the presence of an opioid overdose leading to a higher risk for fatal overdose.


As an older drug, gabapentin has been the focus of much more research than pregabalin so more is known about it. The benefits of gabapentin for opioid tolerance and opioid induced hyperalgesia, for example, are better supported by research than pregabalin.


Gabapentin and pregabalin are prescribed (on- and off-label) for the following conditions:


    Neuropathic (Nerve) Pain

  1. Nerve Pain – Burning, electric, stabbing pains such as seen with sciatica, peripheral neuropathy (diabetic or other types), post-herpetic neuralgia (shingles pain), trigeminal neuralgia, carpal tunnel syndrome and fibromyalgia
  2. Headache prevention
  3. Reduction of opioid induced hyperalgesia (OIH)
  4. Reduction of peripheral and central sensitization including hyperalgesia and allodynia


    Preventing Pain Related to Surgery

  1. Use of a gabapeninoid before, during or just after surgery to reduce post-operative pain, both acutely and chronically


    Sleep Disorders

  1. Insomnia
  2. Restless Leg Syndrome


    Withdrawal Syndromes

  1. Opioid withdrawal
  2. Alcohol withdrawal
  3. Benzodiazepine withdrawal



  1. Anxiety
  2. ADD
  3. Bipolar Disorder





Neuropathic (Nerve) Pain (NP)

The most common reason for prescribing gabapentin and pregabalin is for the management of neuropathic pain (NP). Examples of NP include diabetic neuropathy, post-herpetic neuropathy (PHN), the pain from impinged or irritated nerves in the neck or back pain due to compression from a bulging or herniated disc – such as the shooting pains going down arms or legs (sciatica). Gabapentin and pregabalin are generally considered first-line agents for treating NP but they are only effective in reducing pain severity by 50% or more in about 1/3 of patients.


Another form of gabapentin is Gralise, a time-released version of gabapentin designed to dissolve slowly to allow for enhanced absorption compared with gabapentin immediate-release.  FDA–approved only for the treatment of PHN but used off-label for other neuropathic conditions, Gralise time-release offers the advantage for the patient to achieve higher therapeutic blood levels more quickly over 15 days compared with the usual slower dosing commonly employed with short-acting gabapentin. Gralise also offers the advantage of greater tolerability, especially in people >65 y/o.

See: Neuropathic Pain


Chronic Headache Prevention

Gabapentin and pregabalin are very effective at preventing migraine headaches. They are not prescribed for aborting a headache.

See: Headaches


Reduction of Opioid Induced Hyperalgesia (OIH)

Opioid Induced Hyperalgesia (OIH) is discussed elsewhere at greater length but gabentin and possibly pregabalin may be effective in reducing
the increased sensitivity to pain that is believed to occur in some cases with use of opioids. This hyperalgesia associated with use of opioids shares mechanisms with, and may accompany, central sensitization.

See: OIH


Reduction of Central Sensitization

The presence of chronic pain gives rise to changes in the nervous system that result in increased sensitivity to pain, including hyperalgesia and allodynia, as well as increased sensitivity to other senses including sensitivity to touch, cold and heat, noxious smells, loud sounds, bright lights and emotions. These sensitivities are the hallmark of fibromyalgia but can be found with interstitial cystitis, chronic migraine headaches, irritable bowel syndrome and other conditions associated with chronic pain. Gabapentin and pregabalin are probably the most effective medications available in reducing symptoms arising from central sensitization.

See: Neurobiology of Pain


Reduction in Surgical Pain

A great deal of research is being perfomed in an effort to better understand more about how acute pain becomes chronic. Of particular interest in recent research is exploring ways to reduce the pain associated with surgical procedures, including orthopedic and abdominal surgeries as well as others.


Reduction in Acute Post-Operative Pain

In multiple 2016 reviews of studies evaluating post-operative pain after total knee and total hip arthroplasties (replacements), surgical procedures in which parts of the joints are replaced with artificial parts (prostheses), it was shown that the need for opioids for post-operative pain was reduced when gabapentin was used. The pruritis (itching) associated with the post-operative opioids was also lessened. The dose of gabapentin ranged from 300 mg to 1200 mg before surgery and sometimes right after surgery, though an optimal dose was not identified. Despite the reduction in need for opioids for pain, the pain scores were not significantly different.


A 2011 study evaluating post-operative pain after lumbars discectomies and laminectomies revealed similar results with reductions in post-operative pain, use of opioids and pruritis when gabapentin (1200 mg) and Lyrica (300 mg) were provided in the 24 hours preoperatively.


Additional studies evaluating post-operative pain with abdominal and vaginal hysterectiomies, gall bladder surgery, tonsillectomies and breast surgery also described similar benefts of gabapentin.


Dosing for Post-Operative Pain

The optimal dosages of the two drugs for postoperative pain are still controversial. In postoperative pain studies, gabapentin doses ranged from 300 mg to 1,200 mg, and those for pregabalin ranged from 50 mg to 300 mg. Regardless of their dosages, the adverse effects of both drugs were found to be similar.


Reduction in Chronic Post-Operative Pain

While fewer studies are available, a 2012 review of the literature concluded that perioperative treatment with gabapentin and pregabalin are effective in reducing the incidence of chronic postsurgical pain (CPSP), defined as pain lasting more than 2 months.


Mechanisms of Surgical Pain

It has been reported that the pain occurring after total knee arthroplasty (TKA) is more painful than that of any other orthopedic surgery, including total hip arthroplasty. The mechanism of postoperative pain involves the sensitization of peripheral nociceptive nerve terminals and central neurons. It is thought that sensitization of central neurons is more important than peripheral nerve sensitization.

In the past few decades, there has been a substantial improvement in the understanding of the mechanism of surgical pain. Following surgery, the intense influx of pain signal from tissue trauma can exacerbate pain through central and peripheral sensitization, especially central sensitization, in which the excitability and responsiveness of dorsal horn neurons to pain transmission is enhanced.

(see Central Sensitization).


The results of these changes contribute to abnormal pain responses such as pain sensation with non-painful stimuli (allodynia), enhanced pain responses (hyperalgesia) and spread of hypersensitivity beyond injured tissue. Because some of these modulation processes may turn into modification such as enhancement of gene expression, the pain may persist beyond apparent tissue healing, contributing to chronic postsurgical pain syndromes.



In summary, study findings conclude that in postoperative pain management, gabapentin and pregabalin are effective, although additional research is warranted to confirm appropriate dosing amounts and times. Additional studies are needed to explore the long-term benefits as well. Pregabalin 300 mg day−1 and gabapentin 1,200 mg day−1 showed equivalent analgesic, opioid- sparing and adverse effects as well as patient satisfaction.


Note: In an effort to reduce both acute post-operative pain  and the development of chronic post-operative pain, studies are ongoing to identify both pharmacologic and non-pharmacologic means of doing so. Pharmacologic agents that are being explored in addition to gabapentin and pregabalin include tramadol, NSAIDs, clonidine, nefopam and orphenadrine. Non-pharmacologic methods include acupuncture, relaxation therapy, music therapy, hypnosis and transcutaneous nerve
stimulation (TENS) as part of multi-modal approaches of reducing post-operative pain.

See below for more information/publications

Sleep Disorders

Restless Leg Syndrome and Insomnia

While not explored here, gabapentin and probably pregabalin are helpful in certain sleep disorders. Restless Leg Syndrome often responds well to gabapentin and pregabalin. Gabapentin has also been shown to be helpful in the insomnia associated with tapering down or off benzodiazepines such as Xanax, Valium and Klonopin.

See: Sleep


Withdrawal Syndromes

Opioid and Benzodiazepine Withdrawal Syndromes

Again, these uses of gabapentin and pregabalin in treating withdrawal syndromes will not be explored here except to note that these medications may help with some of the opioid withdrawal symptoms associated with markedly reducing or discontinuing the use of chronic opioids. These symptoms  include hyperalgesia, insomnia, anxiety and nausea. Anecdotal reports indicate gabapentin to offer dramatic relief of opioid withdrawal symptoms in individual cases.

Benzodiazepine withdrawal is associated with the risk of seizures, especially Xanax (alprazolam), gabapentin or pregabalin can be helpful in reducing this risk. Most commonly, benzodiazepine withdrawal is associated with insomnia and increased anxiety, both of which can be reduced with the use of gabapentin or pregabalin.


Psychiatric Conditions

General Anxiety

Gabapentin and pregabalin may be effective for the treatment of anxiety, including the anxiety often associated with chronic pain. Doses of pregabalin totaling up to 450 mg/day with split doses of 150-200 mg are effective and well tolerated. Information regarding the use of these medications for other psychiatric conditions is deferred to other resources.


Dosing – Gabapentin & Lyrica

Gabapentin comes as a capsule, tablet, or liquid. It is usually taken with a full glass of water (8 oz) three times a day and may be taken with or without food. Pregabalin comes only in capsules or liquid and can be taken 2 or 3 times/day.Take the medication at evenly spaced times throughout the day and night; do not let more than 12 hours pass between doses. It may take several weeks before a dose is established that provides relief of symptoms. Be patient and do not give up prematurely! Your doctor will start you on a low dose and gradually increase your dose as needed to treat your condition.


To avoid side effects when you first start these medications, take the medication as follows:

– Start with one tablet/capsule at night only, for 3 nights then

– Add a second tablet/capsule in the morning and take twice daily for 3 days then

– Take one tablet/capsule 3x/daily


Once you are comfortable taking gabapentin/pregabalin one tablet/capsule 3x/day for a week or two, you can gradually work your dosing up to 2 tablet/capsules 3x/day for a week or two. Reassess your benefits at this time – if 2 tablets/capsules 3x/day offers more benefit than 1, consider increasing your dose to 3 tablets/capsules 3x/day for possible further benefit and so on. In general, a dose of 400mg 3x/day is the usual minimum dose to achieve pain benefit. With gabapentin, if no benefit is recognized at a dose of 900 mg 3x/day, there is little reason to continue additional trials at higher doses.  


The usual maximum dose of gabapentin is 1200 mg 3x/day and the usual maximum dose of pregabalin is 200mg 3x/day. With pregabalin, the total daily dose can be divided into twice daily rather than 3x/day if preferred. If you encounter side effects as you increase your doses, drop your dose down to the lower dose that did not give side effects. Do not increase your dose if you are already experiencing side effects at your current dose. The goal is to identify the dose that gives you the maximum benefits with no side effects.


If your doctor tells you to take one-half of a tablet as part of your dose, carefully split the tablet along the score mark. Use the other half-tablet as part of your next dose. Properly dispose of any half-tablets that you have not used within several days of breaking them.

Dosing for Gralise:
Day 1:    300mg
Day 2:    600mg
Day 3-6: 900mg
Day 7-10:   1200mg
Day 11-14: 1500mg
Day 15:      1800mg

Dosing – Kidney Disease (Renal Insufficiency)

Gabapentin (Neurontin) and Pregabalin (Lyrica)

Because gabapentin and pregabalin are not metabolized by the liver and are  eliminated solely through the kidney, kidney disease may poses a risk for gabapentin and pregabalin accumulation and toxicity. For example, gabapentin’s half-life is approximately 5-7 hours but in patients with kidney dysfunction that period of time may extend to 132 hours. In patients on dialysis, gabapentin and pregabalin will be filtered out, so supplementary dosing after dialysis may be needed and should be guided by the dialysis specialist. In gabapentinoid toxicity, neurotoxicity can present as dizziness, unsteady gait, nystagmus (abnormal eye movements), tremor, severe muscle spasms, drowsiness, confusion and coma. Your prescribing physician should adjust gabapentin and pregabalin dosing based on level of kidney function as measured by creatinine clearance. If you have any history of kidney problems. be certain to notify your physician.


Discontinuing Gabapentinoids

Do not suddenly stop taking these medications – if you suddenly stop taking gabapentin or pregabalin after being on it for a while, you may experience withdrawal symptoms such as anxiety, difficulty sleeping, nausea, and sweating – however, withdrawal symptoms are very uncommon. To avoid these withdrawal symptoms when you discontinue gabapentin or pregabalin, you should decrease your dose gradually over about a week (unless the problem is an allergic reaction, then immediately stop it).


What should I
do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.


What special precautions should I follow?

* tell your doctor and pharmacist if you are allergic to gabapentin/pregabalin or any of the inactive ingredients in the medicine. Ask your pharmacist for a list of the inactive ingredients.

* tell your doctor and pharmacist what prescription and non-prescription medications, vitamins, nutritional supplements and herbal products you are taking or plan to take.

* if you are taking antacids such as Maalox or Mylanta, take them at least 2 hours before you take gabapentin/pregabalin.

* tell your doctor if you have or have ever had seizures or kidney disease.

* tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding.

* if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking gabapentin/pregabalin.

* gabapentin or pregabalin may make you drowsy or dizzy. Do not drive a car or operate machinery until you know how this medication affects you and remember that alcohol, pain medications and sedatives can add to the drowsiness caused by this medication.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store the tablets and capsules at room temperature, away from excess heat and moisture (not in the bathroom). Store the liquid in the refrigerator. Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.



What side effects can Gabapentin & Lyrica cause?

(Do not be alarmed at the following list – they represent potential side effects, not expected side effects)

Most of these symptoms are also listed for other medications you may already be taking – including narcotic pain medications, and anxiety medications. In most cases these side effects will be avoided by starting at a low dose and increasing the dose slowly. And even if side effects do occur, they will almost always go away when you reduce the dose of the medicine. Statistically, these medications are well tolerated by most patients: less than one out of ten patients discontinue these medications because of intolerable side effects.


If you do experience persistent side effects as you increase your dose, reduce your dose to the previous dose that you tolerated well. After a few days, try increasing the dose again. If you still experience intolerable side effects, return again to the previous dose you tolerated well and stay at that dose until you speak with your doctor again.


Tell your doctor if any of these symptoms are severe or do not go away:


   Common side effects:

   * drowsiness

   * tiredness or weakness

   * dizziness or unsteadiness


Unusual side effects:

   * headache

   * shaking of a part of your body that you cannot control

   * double or blurred vision

   * anxiety

   * memory problems

   * strange or unusual thoughts

   * unwanted eye movements

   * heartburn, nausea, diarrhea or constipation

   * dry mouth

   * weight gain

   * swelling of the hands, feet, ankles, or lower legs

   * rash or itching


Gabapentin (Neurontin) or Lyrica (pregabalin) may cause other side effects. Notify your doctor if you have any unusual symptoms while taking this medication. Some symptoms may be serious especially when due to an allergic reaction. If you experience any of the following symptoms, call 911 immediately:


   * swelling of the face, throat, tongue, lips, eyes, or extremities

   * hoarseness

   * difficulty swallowing or breathing

   * seizures (usually only in people taking gabapentin for seizures who suddenly stop the gabapentin)


In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911. Symptoms of overdose may include:


   * double vision

   * slurred speech

   * drowsiness

   * diarrhea


Neurobiology of the Gabapentenoids

Shared Mechanisms with Opioids

Opiates act by bonding to opioid receptors, opening
G protein-coupled potassium channels, and closing voltage-dependent calcium channels, which results in the prevention of the release of excitatory amino acids in the spinal cord which interact with the N-methyl-d-aspartic acid (NMDA) receptor. Gabapentin selectively inhibits voltage-gated calcium channels, increases GABA transmission, and modulates excitatory amino acids at N-methyl-d-aspartic acid (NMDA) receptor sites. Thus opiates and gabapentin have certain shared mechanisms affecting analgesia. There is some research that also suggests that gabapentin reverses microglial activation in the spinal cord and this represents a mechanism for many of the benefits noted with gabapentin.


Therefore, although gabapentinoids are sometimes classified as “calcium channel blocking agents, this does not entirely reflect their mechanisms of action. They are more accurately described as drugs that depress neuronal excitability by a variety of mechanisms.


It has also been hypothesized that an increased analgesic benefit of gabapentin and morphine when taken together may occur  due to an increase in gabapentin serum concentration that results from the two medications being given together. Although the mechanism(s) by which this may occur is uncertain, it appears that two different sites for this interaction – one at the level of absorption and the other at the level of elimination. Gabapentin’s usefulness in preventing opioid withdrawal is probably due to modulating excitatory amino acids which are increased during withdrawal.


Descending Nerve Pathways

Recent research in the last few years has called into question how gabapentin helps with neuropathic pain. Until recently, the focus of understanding of gabapentinoids’s mechanism of action in reducing pain has been their action on the Ca channel on nerves in the spinal cord. However, it is now believed that gabapentinoids may reduce neuropathic pain through its action at the locus coeruleus (LC) in the midbrain. The LC is the site of the origin of nerve pathways that descend from the brain to the spinal cord (dorsal horn) where (most) of these pathways act to inhibit pain signals from ascending pathways in the dorsal horn to the brain to reduce the experience of pain.


More specifically, gabapentinoids inhibits presynaptic γ-aminobutyric acid GABA release and induces glutamate release from astrocytes (glial cells) in the locus coeruleus (LC), which increase LC neuron activity in the descending pathways resulting in increased noradrenaline release in the dorsal horn of the spine. Noradrenaline reduces pain via multiple mechanisms in the dorsal horn via actions on both neurons and immune cells:


1. Neuronal Mechanisms

Noradrenaline stimulates both pre- and postsynaptic α2-adrenergic receptors. Stimulation of presynaptic α2-adrenergic receptors on primary nociceptive neurons inhibits voltage-gated Ca2+ channels, thus reducing the release of excitatory neurotransmitters (i.e., glutamate and substance P) which are players in the activation and maintainence of chronic pain. In addition, activation of postsynaptic α2-adrenergic receptors on secondary sensory neurons in the spinal cord results in reduction of neuronal excitability and a decrease in ascending pain signal transmission.


2. Neuroinflammatory Mechanisms

Noradrenaline action on glial cells to reduce neuroinflammation is another mechanism by which it reduces neuropathic pain. Neuroinflammation plays a primary role in the development of chronic pain. Neuroinflammation is characterized by infiltration and activation of glial cells (astrocytes and microglia), the immune cells in the CNS.  Peripheral damage and hyperactivity of primary sensory neurons induce neuroinflammation through glial cell activation which releases pro-inflammatory cytokines (e.g., TNF-α and IL-1β), chemokines, glutamate, and reactive oxygen species.


These glial mediators modulate nerve transmission in the spinal cord and enhance pain neurotransmission, ultimately leading to central sensitization and the transition from acute to chronic pain. Both astrocytes and microglial cells in the spinal cord have α2-adrenoceptors, and several studies have shown that stimulation of these receptors by noradrenaline reduces glial activation and reduces chronic inflammation and pain.


Implications for multi-modal drug therapy for neuropathic pain

While gabapentinoids activate the LC resulting in increased noradrenaline levels in the spinal cord, antidepressants (ADs) including the tricyclic ADs and especially duloxetine (Cymbalta, an SNRI) also increase noradrenaline levels in the spinal cord by inhibiting reuptake of noradrenaline at nerve synapses.  This leads to the premise that gabapentinoids and ADs, especially duloxetine may work synergistically when taken together for neuropathic pain.


Additionally, clonidine, an alpha-2 adrenergic receptor agonist, is known to reduce neuropathic pain and may offer further potential for synergy when taken with gabapentinoids. Although there is some evidence for supraspinal and peripheral sites of action, it is believed that clonidine’s primary mode of analgesic activity is at the dorsal horn of the spinal cord. Tizanidine is another a-2 agonist, similar to clonidine, but has some important differences. Like clonidine, it has sedative, anxiolytic, and analgesic properties, but it has a shorter duration of action and less effect on heart rate and blood pressure. Tizanidine has been shown to have benefit in the treatment of painful muscle spasms in the neck and shoulder.

See: Alpha-2 Adrenergic Agonists


Tapentadol (Nucynta) is an opioid
that also acts on the descending pathways leading to increased noradrenaline in the dorsal horn. Because of its activity on the descending pathways it provides greater pain benefit with less reliance on the opioid system to achieve pain control. This leads to reducd opioid-related side effects compared to other opioids.

See: Tapentadol (Nucynta)


With prolonged time after neuropathic injury, noradrenergic neurons in the LC may become less responsive to gabapentinoids, leading to impaired gabapentinoid analgesia. Astroglial glutamate dysregulation is critical to this impaired LC response. Recent animal studies confirm that the function of the descending noradrenergic inhibitory system is impaired in chronic pain states, with the potential for reduced response to gabapentinoids.


It has been suggested that when facing a reduced clinical response to gabapentinoids, the addition of an antidepressant such as duloxetine (Cymbalta) and/or an alpha-2 adrenergic receptor agonist such as clonidine (Catapres) or tizanadine (Zanaflex) may help restore effectiveness of the gabapentinoid. Furthermore, there may be a synergistic benefit for the use of tapentadol (Nucynta).



Additional studies suggest that histone deacetylase inhibitors and may restore the impaired noradrenergic descending inhibitory system through their action on noradrenergic neurons in the LC. The drug valproate is known to increase glutamate transporter-1 (GLT-1) activity in the LC, increasing glutamate levels, and may restore gabapentin analgesia when impaired in patients with long term chronic nerve pain.


Unfortunately, the research described above remains pre-clinical and has not been replicated in human studies. Studies are lacking that evaluate the combination of gabapentinoids, ADs and/or valproate and clonidine and there are no human studies that offer evidence to guide one in which of these drugs should be started first or how a second or third drug may be added or recommendations for dosing when combination therapy is initiated. One article published in 2009 did demonstrate a synergy with gabapentin and nortriptyline, a tricyclic antidepresant, for neuropathic pain.




Gabapentin – New Articles

  1. Descending Noradrenergic Inhibition An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain – PubMed – 2018
  2. Analgesic mechanisms of gabapentinoids and effectsin experimental pain models – a narrative review – 2018
  3. Gabapentin Reverses Central Hypersensitivity and Suppresses Medial Prefrontal Cortical Glucose Metabolism in Rats with Neuropathic Pain – 2014
  4. Advances in Pain Research – Mechanisms and Modulation of Chronic Pain – 2018 Book
  5. Gabapentin loses efficacy over time after nerve injury in rats – Role of glutamate transporter-1 in the locus coeruleus – 2016
  6. Gabapentin for chronic neuropathic pain and fibromyalgia in adults – 2014
  7. Evaluation of the Effect of Gabapentin on Tendon Healing in an Experimental Rat Model – 2020


Gabapentin – Overviews

  1. The Anti-Allodynic Gabapentinoids – Myths, Paradoxes, and Acute Effects – 2016
  2. Interchangeability of generic topiramate and gabapentin


Gabapentin – Alcohol Withdrawal

  1. A Double Blind Trial of Gabapentin vs. Lorazepam in the Treatment of Alcohol Withdrawal – 2009

 Gabapentin – Insomnia

  1. An Open Pilot Study of Gabapentin vs. Trazodone to Treat Insomnia in Alcoholic Outpatients – 2003
  2. Pharmacokinetic effects of simultaneous administration of single-dose gabapentin 500 mg and zolpidem tartrate 10 mg in healthy volunteers – 2015
  3. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 28-Day, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance – 2014
  4. A Randomized, Double-Blind, Single-Dose, Placebo-Controlled, Multicenter, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance – 2014
  5. The absorption of gabapentin following high dose escalation. – PubMed – NCBI
  6. Gabapentin increases slow-wave sleep in normal adults – 2002
  7. Treatment effects of gabapentin for primary insomnia – 2010

 Gabapentin – Dosing in Kidney Disease

  1. gabapentin-toxicity-in-patients-with-chronic-kidney-disease-2013


Gabapentin – Neurobiology

  1. Implications and mechanism of action of gabapentin in neuropathic pain. – PubMed – NCBI
  2. Pain relief by gabapentin and pregabalin via supraspinal mechanisms after peripheral nerve injury. – PubMed – NCBI
  3. Gabapentin reverses microglial a
    ctivation in the spinal cord of streptozotocin- induced diabetic rats – 2009
  4. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. – PubMed – NCBI


Gabapentin – Neurobiology, Descending Pathways

  1. Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System – 2019
  2. Descending Noradrenergic Inhibition – An Important Mechanism of Gabapentin Analgesia in Neuropathic Pain – 2018
  3. Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms – 2014
  4. Monoamines as Drug Targets in Chronic Pain – Focusing on Neuropathic Pain – 2019
  5. Nortriptyline and Gabapentin, Alone and in Combination for Neuropathic Pain- A Double-Blind, Randomised Controlled Crossover Trial – 2009
  6. Up-regulation of spinal glutamate transporters contributes to anti-hypersensitive effects of valproate in rats after peripheral nerve injury – 2011



Gabapentin & Lyrica – Opioid Interactions

  1. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids – 2019
  2. Oxycodone-induced tolerance to respiratory depression – reversal by ethanol, pregabalin and protein kinase C inhibition – 2018


Gabapentin – Opioid Induced Hyperalgsia (OIH)

  1. Opioid-induced hyperalgesia in chronic pain patients and the mitigating effects of gabapentin – 2015
  2. The median effective dose of ketamine and gabapentin in opioid-induced hyperalgesia in rats: an isobolographic analysis of their interaction. – PubMed – NCBI
  3. Gabapentin improves Cold-pressor Pain Responses in Methadone-maintained Patients – 2013


Gabapentin – Opioid Withdrawal

  1. Gabapentin Effect on Pain Associated with Heroin Withdrawal in Iranian Crack – 2012
  2. Gabapentin for Opioid Withdrawal Anecdotal account – Erowid 2009
  3. Role of gabapentin in preventing fentanyl- and morphine-withdrawal-induced hyperalgesia in rats. – PubMed – NCBI


Gabapentin – Pain

  1. Antiepileptic drugs for neuropath… [Cochrane Database Syst Rev. 2013] – PubMed – NCBI
  2. Antidepressants and Antiepileptic Drugs for Chronic Non-Cancer Pain
  3. Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: current evidence and future directions. – PubMed – NCBI
  4. Gabapentin for chronic neuropathi… [Cochrane Database Syst Rev. 2014] – PubMed – NCBI

Gabapentin – Respiratory Depresson

  1. Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids – 2019
  2. Oxycodone-induced tolerance to respiratory depression – reversal by ethanol, pregabalin and protein kinase C inhibition – 2018

 Gabapentin – Substance for Abuse

  1. Gabapentin misuse, abuse and diversion – a systematic review – 2016</li >
  2. Review about gabapentin misuse, interactions, contraindications and side effects – 2017


Anxiety – Gabapentin (Neurontin) & Lyrica (pregabalin)


Anxiety – Lyrica

  1. Pregabalin in acute treatment of anxious depression – 2013
  2. Pregabalin in Generalized Anxiety Disorder – A Placebo-Controlled Trial – 2003
  3. The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic – 2007
  4. Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. – PubMed – NCBI no higlights
  5. Pregabalin – A guide to its use in fibromyalgia, neuropathic pain and generalized anxiety disorder – 2014
  6. Pregabalin in the Management of Painful Diabetic Neuropathy – A Narrative Review – 2019


Anxiety – Gabapentin

  1.  Gabapentin – long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders – 1998

Neuropathic Pain

Neuropathic Pain – Overviews

  1. What is Neuropathic Pain? UW Health – 2010
  2. Pathophysiological Mechanisms of Neuropathic Pain – 2011, no highlights
  3. A Primer on Scientific Evidence and Treatment of Neurogenic Pain

Neuropathic Pain – Central and Peripheral Sensitization

  1. Peripheral and Central Mechanisms of Pain Generation_ 2006


Neuropathic Pain – Treatment Overviews

  1. Management of Neuropathic Pain
  2. Pharmacologic Treatments for Neuropathic Pain
  3. Pharmacological management of chronic neuropathic pain – Revised consensus statement from the Canadian Pain Society – 2014
  4. Clinical practice guidelines for the management of neuropathic pain – a systematic review -2016
  5. Pharmacological Treatment Of Diabetic Peripheral Neuropathy – 2015
  6. Neuropathic pain – mechanisms and their clinical implications – 2014
  7. Treatment_of_Neuropathic_Pain_The_Role_of_Unique_Opioid_Agents_-_2016
  8. Opioids and Neuropathic Pain – 2012
  9. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US – 2017

    Preventing Pain Related to Surgery – Gabapentin & Pregabalin

  1. Do surgical patients benefit from perioperative gabapentin:pregabalin? A systematic review of efficacy and safety. – PubMed – NCBI
  2. Perioperative administration of gabapentin 1,200 mg day−1 and pregabalin 300 mg day−1 for pain following lumbar laminectomy and discectomy – 2011
  3. Preemptive use of gabapentin in abdominal hysterectomy: a systematic review and meta-analysis. – PubMed – NCBI
  4. The Effect of Gabapentin on Acute Postoperative Pain in Patients Undergoing Total Knee Arthroplasty – 2016
  5. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. – PubMed – NCBI
  6. The use of gabapentin in the management of postoperative pain after total hip arthr
    oplasty – 2016
  7. The use of gabapentin in the management of postoperative pain after total knee arthroplasty – 2016
  8. Use of gabapentin for perioperative pain control – A meta-analysis – 2007
  9. The efficacy of gabapentin:pregabalin in improving pain after tonsillectomy: A meta-analysis. – PubMed – NCBI
  10. Effects of gabapentin on postoperative pain, nausea and vomiting after abdominal hysterectomy: a double blind randomized clinical trial. – PubMed – NCBI
  11. Gabapentin and postoperative pain – a systematic review of randomized controlled trials 2006 – PubMed Health
  12. Preoperative Preemptive Drug Administration for Acute Postoperative Pain – A Systematic Review And Meta-Analysis – 2016
  13. the-effects-of-preoperative-oral-pregabalin-and-perioperative-intravenous-lidocaine-infusion-on-postoperative-morphine-requirement-in-patients-undergoing-laparatomy-2015
  14. perioperative-pain-management- 2007 pubmed-ncbi
  15. optimizing-pain-management-to-facilitate-enhanced-recovery-after-surgery-pathways 2015 -pubmed-ncbi

    Preventing Pain Related to Surgery – other medications

  1. perioperative-pain-management- 2007 pubmed-ncbi
  2. optimizing-pain-management-to-facilitate-enhanced-recovery-after-surgery-pathways 2015 -pubmed-ncbi
  3. neuronal-sensitization-and-its-behavioral-correlates-in-a-rat-model-of-neuropathy-are-prevented-by-a-cyclic-analog-of-orphenadrine-pubmed-ncbi
  4. genotyping-test-with-clinical-factors-better-management-of-acute-postoperative-pain-2015
  5. the-impact-of-genetic-variation-on-sensitivity-to-opioid-analgesics-in-patients-with-postoperative-pain-a-systematic-review-and-meta-analysis-2015
  6. development-of-a-management-algorithm-for-post-operative-pain-mapp-after-total-knee-and-total-hip-replacement-2014
  7. nefopam-after-total-hip-arthroplasty-role-in-multimodal-analgesia-pubmed-ncbi
  8. nefopam-analgesia-and-its-role-in-multimodal-analgesia-a-review-of-preclinical-and-clinical-studies-pubmed-ncbi
  9. preventive-analgesic-efficacy-of-nefopam-in-acute-and-chronic-pain-after-breast-cancer-surgery-2016

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Please note also, that many of the benefits for medications described on this web site include “off-label” use for a medication. Off-label prescribing refers to the use of medication for a condition not named in its FDA approval. Physicians are free to prescribe any medication they want, as long as there is some evidence for usefulness. And remember that the lack of an FDA indication does not necessarily mean lack of efficacy—it sometimes means that no drug company has deemed the investment in clinical trials worth the eventual pay off.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


Supplements recomm
ended by Dr. Ehlenberger may be purchased commercially
online or at Accurate Clinic.

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

Accurate Supplement Prices