Pregabalin - a wide-ranging medication - deNovo Medica
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Pregabalin – A wide-
ranging medication
Introduction
Pregabalin was used initially as an anxiolytic in the 1990’s and trials were conducted
in panic disorder, amongst others. Since then, it was introduced in South Africa as a
drug for neuropathic pain, registered only for use in diabetic neuropathy and post-
herpetic neuralgia.
DR MS Salduker
(MBChB)(FCPsych) KEY MESSAGES
Psychiatrist
Durban, Kwa-Zulu Natal
• Understanding pregabalin’s mechanism of action, supporting the wider use of this agent in
specific pain and anxiety conditions
• Chronic pain management in difficult-to-treat patients is guided by attaining 3 initial goals –
exogenous opiate removal, reduction in nervous system excitability and restoration of ‘normal’
sleep patterns
• Other specific conditions that will benefit from pregabalin use are described in a practice-
orientated manner, including generalised anxiety disorder, functional pain associated with
irritable-bowel syndrom, tension-type headaches and mechanical back pain
• Optimal approaches to the introduction and dosing of pregabalin are described, based on
clinical experience, so as to limit side-effects and treatment discontinuation
This report was made possible
by an unrestricted educational
grant from Cipla. The content
of the report is independent of
the sponsor.
January 2018 I 1
Pregabalin – A wide-ranging medication
Sensory cortex Limbic system
Gabapentin/pregabalin
α2δ subunit
Enhanced Calcium
locus ceruleus Nociceptive
activation neuron
Enhanced P/Q type
descending voltage gate Inhibitory
noradrenergic calcium noradrenergic
inhibition channel neuron
Painful
stimulus
Nociceptive Postsynaptic
neuron neuron
Figure 1. Mechanism of action1
Mechanism of action
“Pregabalin has The mechanism of action and potential presynaptic neurone, thereby inhibiting
utility of pregabalin is widespread and the release of dopamine, norepinephrine,
a wide-ranging the off-label uses currently far outnumber serotonin, substance P and glutamate. It
utility in areas of the registered ones. Other countries have has no effect on gamma-aminobutyric
registered it for use in anxiety disorders acid (GABA) receptors or metabolism.
pain, anxiety and and in the EU it is one of the most pre- The effect of pregabalin is similar to
neuromodulation.” scribed drugs for anxiety, providing a safe gabapentin but six times more powerful
alternative for the benzodiazepines and at the receptor site. Logically therefore
the attendant problems with this class. it would make sense that pregabalin has
It has also been shown to be a safe anti- a wide ranging utility in areas of pain,
epileptic and effective in a wide range of anxiety and neuromodulation. Multiple
chronic pain conditions especially those studies have been carried out to ascertain
that fall into the functional pain category. the effect of administering pregabalin in
To understand this use, one has to under- peri-operative settings and the consensus
stand the mechanism of action of this is that, if administered pre-operatively, it
drug, which is not dissimilar to gabapen- has great benefit in reducing post-oper-
tin in action (Figure 1). ative pain and the need for opiates and
These drugs work via the Ca2+ chan- nonsteroidal anti-inflammatory drugs
nels which are involved in transmission (NSAIDs).2 Similarly, many trials of pre-
of nerve signal via an effect on polar- gabalin in anxious patients have indicated
ity. This then has an effect on the excit- its effects vs. placebo are comparable to
ability of the nerve and, as a result, the benzodiazepines. The obvious advantage
Earn free eventual conduction of the signal. This of pregabalin is the relative lack of toler-
CPD Points effect is a widespread one, acting in the ance and dependence which the benzodi-
peripheral nervous system (PNS), the spi- azepines produce. In Europe, pregabalin
Join our CPD community at nal cord and even in the brain tissue. The is the most prescribed drug for anxiety
mechanism of action is thought to occur and preferred to the benzodiazepines for
www.denovomedica.com via attaching to the alpha-2 delta subunit the same reasons.
of the voltage gated Ca2+ channels in the
and start to earn today!
Chronic pain management
In my experience, running a chronic pain of those difficult patients whom all other
clinic in Durban, KZN; pregabalin has specialists have written off. The typical
become the cornerstone of management type of patients referred to us as pain
2 I January 2018
Pregabalin – A wide-ranging medication
specialists are those who have been living or very tolerant to the effects of opiates,
with pain for years and whose entire eco- having run the gauntlet of almost all of
system has evolved to adapt to the pain. their variants. Then they have the added
Their origins may differ but their paths complication of being clinically anxious
all merge at the point of mood, anxiety and depressed both as a co-morbidity of
and poor quality of life and productivity. the pain as well as the effect of long term
The effect is, of course, more far-reaching opiate use. They also are victims of the
than their personal domains – families, opioid rebound syndrome where the exog-
marriages, friends etc. are all affected in enous opiates suppress the endogenous
some way. In order to understand this (endorphin) production, thereby reduc-
link, one has to understand the context ing the pain threshold and making them
in which the pain presents. These are susceptible to hyperalgesia and allodynia.
patients who are generally dependant on
Physiology of chronic pain
Physiologically, the nervous system is then represents an abnormal chemical
chronically hyperactive from the PNS milieu into which the clinician attempts
to the spinal tracts to the thalamus and to introduce traditional pain medications
the cortical structures. The manifestation like NSAIDs, opiates and paracetamol.
of this hyperactivity is the physical and This approach does not work. The fun-
psychological symptoms of pain and agi- damental principal therefore has to be the
“The reduction of tation. It stands to reason that the GABA- attempt to return this abnormal chemical
glutamate balance is disrupted, as the state to one resembling a normal balance
afferent signals excitability clearly is in the ascent and the before pain control can be achieved.
from the periphery inhibitory influence is overwhelmed. This
and reduction in
pain perception Clinical approach to chronic severe pain
is an integral Fundamental goals that need to be
achieved in the management of chronic Box 1. Fundamental goals of chronic
part of managing severe pain are three-fold (Box 1). By severe pain management
the chronic pain removing all exogenous opiates, the
1. Remove all exogenous opiates
endogenous system can reset itself.
phenomenon.” Reducing conduction at all levels of the 2. Reduce state of excitability
nervous system (peripheral, spinal and
cortical) reduces the state of excitability. 3. Ensure good sleep and return of circadian
In a recent review article on the state of rhythm to as close to normal as possible
nociception and pain research, Baliki
and Apkarian (2015) pointed out that
the reduction of afferent signals from the The role of pregabalin in this approach
periphery and reduction in pain percep- is three-fold: it reduces nerve conduc-
tion is an integral part of managing the tion in the PNS and central nervous
chronic pain phenomenon. They also system (CNS), it has an anxiolytic effect
stressed that the onset of chronic pain and it has an effect on sleep architec-
syndromes and transition from acute ture increasing slow wave sleep. In the
to chronic pain is largely a central issue absence of opiates and combined with
associated with anxiety, mood and other a serotonin-norepinephrine reuptake
pre-existing predispositions.3 Sleep is an inhibitor (SNRI) such as duloxetine and a
integral part of pain management as an safe non-addictive sedative hypnotic, the
increase in the amount of slow wave sleep nett effect is significant. Duloxetine also
has been shown to have the best effect on improves anxiety and mood and reduces
pain control. Ensuring good sleep and pain impulses from entering the thalamus
return to as-normal-as-possible circadian by a spinal inhibition action.
rhythm enables the brain to do all its heal-
ing during sleep, cleaning up the “debris”
from the previous day.
January 2018 I 3
Pregabalin – A wide-ranging medication
Other areas of clinical utility for pregabalin
Pre-operative pain management in chronic pain patients
Pregabalin is used pre-operatively in risk to have ongoing chronic pain post-
chronic pain patients who are most likely operatively; especially with a history of
going to have more than expected lev- opiate use for a prolonged period. These
els of post-operative pain. Once again, patients would benefit from the initiation
patients who have a history of chronic of pregabalin prior to surgery and contin-
pain syndromes or have been in pain for uation post-operatively as an alternative
a significant amount of time as a result of to the opiates.
the pathology, should be regarded as high
Detoxification of benzodiazepine addiction
Because of it’s benzodiazepine-like effect, off this group of drugs, we have had to use
pregabalin is used for detoxification from other benzodiazepines with longer half-
benzodiazepine withdrawals and preven- lives in the past (diazepam). Traditional
tion of relapses. It has also shown to be teaching has recommended fairly long-term
anti-epileptic in nature, so it’s utility in use of the replacement benzodiazepine
preventing seizures in withdrawal states is (+/-3 months) and now, with pregabalin,
helpful. The abuse of benzodiazepines is a this can be avoided as coming off the pre-
worldwide phenomenon and to get patients gabalin is not as problematic.
Benzodiazepine-contraindicated anxiety disorders
The basis of treatment in anxiety disor- great alternatives to this group of drugs.
ders is still primarily the selective sero- Pregabalin has utility in generalised anxi-
tonin reuptake inhibitors (SSRIs). There ety disorder (GAD) where traditional
are patients that respond well to SSRIs approaches are not sufficient and the use
and don’t need much else. However, the of a benzodiazepine is contraindicated.
very nature of anxiety sometimes makes With the registration of pregabalin for
the period of initiating SSRIs difficult, as use in anxiety disorders in Europe, it has
these patients are more unlikely to tolerate grown in stature for this very large group
the side effects and the adjustment period. of patients. The advantages cited in the
This is often when clinicians use benzo- clinical trials have been the rapid onset of
diazepines for a short period, usually two action, improvement of physical symp-
weeks, until the SSRI kicks in. Longer use toms associated with anxiety and the tol-
of the benzodiazepine is discouraged due erability of the drug.4,5 Pregabalin is used
the risk of the patient becoming abnor- not only as an adjunctive treatment, but
mally dependant on the immediacy of the also as monotherapy in GAD.
effect. Traditionally, there have not been
Phantom limb syndrome
The literature on pregabalin efficacy for The addition of a serotonin and norep-
Earn free phantom limb syndrome in amputees is inephrine reuptake inhibitor (SNRI) anti-
CPD Points equivocal, but there is anecdotal evidence depressant is recommended, duloxetine
that shows some utility: “In my pain prac- preferably, as there is a synergism between
Join our CPD community at tice, many patients with phantom pain have these two drugs. One has to bear in mind
responded well to pregabalin.” Having said that the pain may well be related causally
www.denovomedica.com that, there is also a subgroup of amputees and co-morbidly with clinical depression
or paralysed patients who have not bene- and often post-traumatic stress disor-
and start to earn today!
fited from the drug. In the final analysis it der (PTSD), so the antidepressant serves
is an agent worth a try in this population.6 many roles.
4 I January 2018Pregabalin – A wide-ranging medication
Functional pain syndrome
Functional pain syndromes such as irri- Pregabalin provides a treatment that
table bowel syndrome (IBS), chronic pel- will address the pain and the anxiety that
vic congestion, tension-type headache most of these patients have. It must be
(TTH) and mechanical back pain are all remembered that most of these functional
generally associated with muscular tone pain syndromes are related to a central
but have a significant neuropathic ele- pathology around pain sensitivity and,
ment. Once again the general view is that after a period of time, peripheral hyper-
these patients have a high neural tone activity then leads to increased spinal
both centrally and peripherally and are activity. The utility of pregabalin lies in its
traditionally very resistant to most forms ability to reduce nerve conductivity in the
of treatment. These patients also end up periphery and spinal column as well as its
becoming opiate dependant as a result of effect in the brain via the GABA system.
being non-responsive to other treatments.
Fibromyalgia
Fibromyalgia pain syndrome (FPS) most perpetuating the pain and delaying recov-
classically demonstrates the effect of pre- ery. These patients have a high incidence
gabalin in the CNS and PNS. The com- of mood and anxiety disorders and the
bination of duloxetine and pregabalin is origin is becoming more accepted as cen-
considered first-line treatment worldwide tral in nature. At the pain clinic we com-
for this condition (even though we don’t bine physical therapies, psychotherapies
have registration in South Africa). This and medications in order to get the best
therapy, the correction of sleep patterns relief. It must be noted that many patients
and introduction of appropriate exercise who present like with fibromyalgia-like
regimens are the best approach to this symptoms may well have somatoform dis-
ubiquitous condition. orders and making this distinction saves a
Doctors are still mistakenly prescribing lot of unnecessary medicating.
long-term opiates to these patients thereby
Optimal dosing with Pregabalin
The utility of this compound has been in “I often start at 25mg nocte and increase
no doubt, especially in the fields of pain to BD and slowly get up to 75mg BD
management and anxiety. The risks asso- where there is often a significant response
ciated with its use are related to dosing for pain management. From 75 to 150mg
and specific vulnerabilities. Pregabalin is an easier transition after a few weeks, as
action has been shown to be optimum at the patients get accustomed to the effect
150mg BD but there is significant utility at of the drug. It also depends on whether
75mg BD and a role for the 25mg dose as there is co-administration with any other
well. It has been demonstrated that a slow sedating agents so be sure to look out
introduction at lower doses and a gradual for opiates or benzodiazepines, the latter
build up of the dose, monitoring effect of which can have a cumulative sedative
along the way, is best to avoid initial side effect in the patient.
effects of sedation and motor instability.
Discontinuation of treatment
The main reasons patients discontinue exercise in order to avoid this becoming
treatment is sedation and imbalance. significant. Pedal oedema, dry mouth,
Over prolonged periods, pregabalin has blurred vision and urinary hesitancy have
also been shown to cause weight gain and also been described, but these are less
patients have to be counselled on life- reported.
style changes specifically around diet and
January 2018 I 5Pregabalin – A wide-ranging medication
Conclusion
Pregabalin has changed the landscape of has to keep this in mind when confronted
pain management in the last few years, with patients where traditional agents
specifically chronic pain, but also acute have failed. Using pregabalin appropri-
pain and prevention of post-operative ately with a knowledge of the effects and
pain. It also has other uses by virtue of its side effects will help get patients through
mechanism of action, which currently are the initiation period.
mostly off-label in South Africa, and one
References
1. Schmidt PC, Ruchelli G, Mackey C, et al. Pregabalin for the treatment of generalized
Perioperative Gabapentinoids: Choice of Agent, anxiety disorder: an update. Neuropsychiatr Dis
Dose, Timing, and Effects on Chronic Postsurgical Treat 2013; 9: 883-892.
Pain. Anesthesiology 2013; 119: 1215-1221. 5. Strawn JR and Geracioti TD. The treatment of
2. Zhang J, Ho KY and Wang Y. Efficacy of generalized anxiety disorder with pregabalin, an
pregabalin in acute postoperative pain: a meta- atypical anxiolytic. Neuropsychiatr Dis Treat 2007;
Earn free analysis. Br J Anaesth 2011; 106(4): 454-462.
3. Baliki MN and Apkarian AV. Nociception, Pain,
3: 237-243.
6. McCormick Z, Chang-Chien G, Marshall
CPD Points Negative Moods, and Behaviour Selection. B et al. Phantom Limb Pain: A Systematic
Neuron 2015; 87(3): 474-491. Neuroanatomical-Based Review of Pharmacologic
Are you a member of 4. Baldwin DS, Khalil A, Masdrakis VG et al. Treatment. Pain Med 2014; 15(2): 292-305.
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