International Journal of Research in Orthopaedics

Maladkar MN et al. Int J Res Orthop. 2020 Nov;6(6):1365-1370

http://www.ijoro.org

DOI: https://dx.doi.org/10.18203/issn.2455-4510.IntJResOrthop20204615
Review Article

A step closer in the management of uncontrolled neuropathic pain:

gabapentin-nortriptyline combination
Manish Nilkanth Maladkar1*, Chitra Mohan Tekchandani2, Raveena Kanyalal Bajaj2

1
Medical and Regulatory Affairs, Scientific Department, Aristo Pharmaceuticals Private Limited, Mumbai,
Maharashtra, India
2
Medical, Scientific Department, Aristo Pharmaceuticals Private Limited, Mumbai, Maharashtra, India

Received: 11 August 2020

Accepted: 17 September 2020

*Correspondence:
Dr. Manish Maladkar,
E-mail: [email protected]

Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Neuropathic pain is extremely distressing as it significantly hampers the performance of daily activities and impedes
overall quality of life. A large number of illnesses are linked with neuropathic pain like radiculopathy, sciatica, diabetes,
herpes infection, spinal injury, stroke, etc. Treating neuropathic pain is challenging as response to the treatment is at
times uncertain and associated with undesirable side effects. Uncontrolled neuropathic pain is observed in large group
of patients receiving current treatment regimen. Almost half of the neuropathic pain patients need more than two drugs
for pain relief. Various clinical trials have demonstrated better efficacy of combination therapy in reducing pain than
monotherapy. Utilizing drug combination with different mechanism of action or acting on two different sites has
demonstrated superior analgesic effect in painful neuropathic condition. The first tier agents recommended by various
guidelines are calcium channel alpha-2-delta ligands and tricyclic antidepressants that act on different pain pathways.
A clinical trial has shown enhanced pain relief with no increase in side effects with the administration of gabapentin
and nortriptyline combination in patients suffering from neuropathic pain. Moreover, symptoms associated with
neuropathic pain like sleep disturbances, altered mood, decreased walking ability, depression and quality of life were
also significantly improved. Hence, combination therapy of gabapentin and nortriptyline offers a pivotal modality in
the management of uncontrolled neuropathic pain.

Keywords: Neuropathic pain, Calcium channel alpha-2-delta ligand, Tricyclic antidepressants, Gabapentin,
Nortriptyline, Combination therapy

INTRODUCTION of touch or oversensitivity, etc. Among these, pain is one

of the most common and troublesome symptoms
The electrochemical signaling in neurons, though a highly experienced by the patient suffering from neuropathy.
complex process, plays a key role in physiological According to the International association for the study of
homeostasis. Any damage to this neuronal signaling pain (IASP), neuropathic pain is defined as ‘pain arising as
network is associated with several adverse repercussions. a direct consequence of a lesion or disease affecting the
Neuropathy is one such consequence that occurs due to somatosensory system.2 Neuropathic pain is witnessed in
nerve injury or compression that affects the normal activity varied clinical conditions, such as radiculopathy, sciatica,
of the nervous system.1 The symptoms associated with diabetes, spinal cord injury, post-surgery, herpes infection,
neuropathy include burning, tingling, numbness, pain, stroke, fibromyalgia, etc.4 It may be classified as
difficulty in walking, pins and needles, reduced sensation peripheral neuropathic pain, central neuropathic pain and

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 Maladkar MN et al. Int J Res Orthop. 2020 Nov;6(6):1365-1370

mixed neuropathic pain depending upon the affected area reuptake inhibitors like fluoxetine and paroxetine as well
of the neurons. Pain associated with neuropathy can also as serotonin norepinephrine reuptake inhibitors like
be classified depending on the duration as acute and duloxetine and milnacipran have shown efficacy in
chronic in nature, the latter is observed in majority of the treating neuropathic pain and could be considered if the
patients.4 It has substantial impact on the patients’ overall first line drugs fail.20 The widely used class of drugs,
quality of life thus, impeding their daily activities. In Tricyclic antidepressants (TCAs) has been recommended
addition to neuropathic pain, the patient experiences by ADA for the management of diabetic neuropathy.15
psychological variations as well, like anxiety and TCAs can be further classified into tertiary amines
depression.5 Taking together, neuropathic pain is a cluster (amitriptyline and imipramine) and secondary amines
of different conditions which has a significant unfavorable (nortriptyline and desipramine). These drugs block the
effect on patients overall health. reuptake of serotonin and norepinephrine thereby increase
the availability of these inhibitory neurotransmitters in the
NEUROPATHIC PAIN MANAGEMENT descending pain pathway which assists in reducing the
neuropathic pain. The secondary amines like nortriptyline
Neuropathic pain is one of the difficult medical ailments are better tolerated than tertiary amines in terms of
to treat and the key aim is reduction of pain. Neuropathic sedation and other side effects.21 The antidepressant effect
pain management necessitates an interdisciplinary is beneficial in chronic neuropathic pain conditions as
methodology that embraces pharmacological as well as depression is a common comorbidity. 22
non-pharmacological interventions. Physiotherapy is a
part of the management of most chronic pain conditions Opioid analgesics along with tramadol constitute second
which aims to improve the patients’ physical activity line agents for neuropathic pain and third line agents
rather than to reduce pain. Since many years several drugs include bupropion, citalopram, lamotrigine, topiramate,
are available in the armamentarium of neuropathic pain topical low concentration drugs such as capsaicin,
management. Numerous systematic reviews have abridged dextromethorphan, memantine and mexiletine.
the available evidences for the treatment of neuropathic Neuropathic pain agents have been tested in one or
pain and guidelines have been published for an organized different types of neuropathic pain settings and
treatment approach. Drug classes, including tricyclic extrapolation of efficacy to different types of neuropathic
antidepressants, calcium channel alpha-2-delta ligands, pain is reasonable and clinically necessary.
opioid analgesics, topical lidocaine and capsaicin have
demonstrated consistent efficacy in several clinical UNCONTROLLED NEUROPATHIC PAIN
studies. Guidelines like IASP, European Federation of
Neurological Societies, Canadian Pain Society, and Mayo In spite of availability of numerous treatment options,
Clinic Proceedings recommend calcium channel alpha-2- neuropathic pain management is still a challenge due to
delta ligands, tricyclic antidepressants and lidocaine several reasons, namely erratic response to the drug, dose
patches as first line agents for the treatment of neuropathic titration leading to intolerable side effects and unaddressed
pain.6-9 In focal neuropathic pain observed in postherpetic comorbid psychological condition. Thus, moderate to
neuralgia, the latter may be considered for the severe level of pain prevails that contributes to the growing
treatment.10,11 Additionally, carbamazepine or incidence of patients suffering from uncontrolled
oxcarbazepine from benzodiazepine class is the drug of neuropathic pain. It refers to pain score greater than or
choice for the treatment of trigeminal neuralgia. equal to 4 in the DN4 (Douleur Neuropathique 4)
questionnaire.23-25
Calcium channel alpha-2-delta ligands have been used
extensively as a primary agent in treating neuropathic Neuropathic pain is associated with the psychological
pain.12 In particular, gabapentin and pregabalin have been comorbidities in major number of patients like sleep
supported by large number of evidences for their efficacy disturbances, depression and anxiety.26 The pain and
and safety in the management of neuropathic pain. The immobility because of neuropathy makes the individual
mechanism involves blocking of the alpha-2-delta subunit anxious regarding the effectiveness of the treatment or
of calcium channel in the ascending pain pathway, limiting depressed as the patient is not able to perform the normal
the release of excitatory neurotransmitter glutamate and day to day activities. Additionally, the social life of a
substance P responsible for pain transmission.13,14 The patient gets disturbed due to many restrictions which are
American diabetes association (ADA), American again stressful for the patient. The management of
association of clinical endocrinologists (AACE) and neuropathic pain involves certain medication linked with
American academy of neurology (AAN) recommend higher degree of side effects which does not allow the up-
gabapentin for management of diabetic neuropathy.15-17 titration of dose for further reduction of pain. Moreover,
Moreover, gabapentin and pregabalin have demonstrated addition of drug from another class with overlapping side
efficacy in reducing anxiety associated with neuropathy effects sounds unacceptable. These factors make the
which improves the therapeutic outcome.18,19 therapeutic approach for neuropathic pain unassured or
Antidepressants are used in confronting neuropathic pain incomplete. Abundant clinical trials have shown the
from a long time and various clinical trials have recognized efficacy of suggested agents in different neuropathic
their role as analgesics in neuropathy. Selective serotonin conditions including diabetic neuropathy, postherpetic

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 Maladkar MN et al. Int J Res Orthop. 2020 Nov;6(6):1365-1370

neuralgia, fibromyalgia, spinal injury, lumbar stenosis, alone in diabetic neuropathy.33 Oral gabapentin and
low back pain. However, the applicability of result ketamine infusion when administered together produces
obtained from a drug for a particular condition to other greater pain relief when compared to oral gabapentin
neuropathic pain disorders is difficult to determine as some alone.34 Duloxetine and pregabalin combination is safe,
types of neuropathic pain patients may respond differently. effective and well tolerated in patients suffering from
Additionally, the association with psychological diabetic neuropathic pain.35 Epalrestat and
comorbidities remains unaddressed while tackling methylcobalamin combination revealed faster and better
neuropathic pain. Thus, uncontrolled neuropathic pain is a neuropathic pain reduction associated with diabetes than
common phenomenon associated with neuropathic pain epalrestat monotherapy.36 Tramadol and acetaminophen
sufferers with an intense impact on patient well-being. A combination is more effective and well tolerated than
definite necessity exists for improving the management of placebo in the management of painful diabetic
uncontrolled neuropathic pain, which should not be neuropathy.37 Faster analgesia is achieved with
restricted to reduce pain but also should be extended to the combination of capsaicin and doxepin topical application
management of psychological symptoms. as compared to a single agent.38

GABAPENTIN AND NORTRIPTYLINE

COMBINATION
Inadequate
efficacy of Clinical study carried out in patients suffering from
treatment neuropathic pain evaluated and demonstrated that
regimen gabapentin and nortriptyline combination is an efficacious
and safe therapy in the management of neuropathic pain.
Gabapentin when given in combination with nortriptyline
significantly reduces neuropathic pain than either of the
single agent. The pain score is found to be significantly
Side-effects of reduced from the second day of administering the
Psychological
the current combination therapy. There is almost 18% greater pain
comorbidities reduction with gabapentin and nortriptyline combination
regimen
therapy as compared to monotherapy. Moreover, the
combination improves depression, mood, sleep
disturbances, walking ability and overall health related
quality of life. Gabapentin and nortriptyline, both have
Figure 1: Reasons of uncontrolled neuropathic pain. some set of common side effects like somnolence and
dizziness but it is demonstrated that the intensity of side
COMBINATION THERAPY IN THE effects do not elevate and are comparable with
MANAGEMENT OF UNCONTROLLED monotherapy of both the drugs when given in
NEUROPATHIC PAIN combination.39 On a wider note, managing uncontrolled
neuropathic pain requires a combination of drugs which
As discussed earlier, current treatment regimen does not enhances or complements the action of other drug and
provide adequate pain relief in many of the neuropathic improves the tolerability profile. Focusing on a potential
pain sufferers. Emphasis for combining two agents is combination of calcium channel alpha-2-delta ligands like
conversed in many literatures and could be a plausible gabapentin and TCAs like nortriptyline acting on
choice for satisfactory pain relief.24,27,28 Combination of complementary pathways provide enhanced pain relief
drugs with different modes of action may be beneficial in without increasing the side effects which further enhances
tackling neuropathic pain in a more effective manner.29 the tolerability of the regimen. Importantly, the
Various trials have demonstrated a potential role of combination of gabapentin and nortriptyline is cited by the
combination therapy furnishing the base for the National institute of health and care excellence (NICE)
employment of dual drug therapy as a cornerstone in the guidelines while considering the treatment strategies.40
management of uncontrolled neuropathic pain. The combination therapy of gabapentin with tricyclic
Additionally, it is reported that 45% of neuropathic pain antidepressants is highly recommended (highest grading)
patients require two or more drugs for their pain relief.30 for the management of neuropathic pain by Danish expert
committee based on scientific evidence and clinical
Several trials have reported that combination of experience.41 Moreover, a consensus statement from
medications substantially reduces more pain than Indian experts also recommends this combination.42 Fixed
monotherapy. Gabapentin in combination with morphine dose combinations especially of gabapentin with
demonstrated better analgesia at lower doses than either nortriptyline can be synergistic and improve treatment
agent administered alone.31 The combination of adherence, especially in Indian setting where compliance
gabapentin and nortriptyline markedly improved pain in to therapy is generally poor.
patients suffering from chronic orchialgia.32 Gabapentin
and oxycodone combination is superior to gabapentin

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 Maladkar MN et al. Int J Res Orthop. 2020 Nov;6(6):1365-1370

The combination of gabapentin and nortriptyline has a nortriptyline is lower than with either of the single agent.44
strong peer reviewed backing with several authors stating Superior results have been obtained with combined
about the advantages of combination. treatment of gabapentin and nortriptyline than each agent
alone in pain control; these agents should be strongly
considered in combination in patients experiencing
inadequate relief on monotherapy.45,46

5.71
6
5

Mean score
4
2.92
3
2
0.72
1
0
Baseline Week 2 Week 4
Duration of treatment
Figure 2: Advantages of combination therapy in
managing uncontrolled neuropathic pain.
Figure 5: Mood score.

7 6.57
7 6.35
6
Mean score

5 3.55 6
4
5
Mean score

3 3.38
2 1.00 4
1 3
0
Baseline Week 2 Week 4 2 0.88
1
Duration of treatment
0
Baseline Week 2 Week 4

Figure 3: Mean pain intensity score. Duration of treatment

7 6.26 Figure 6: Sleep score.

6
A post-marketing surveillance was conducted in 494
5
Mean score

Indian diabetic neuropathy patients treated with

4 3.35 gabapentin 300 mg- nortriptyline 10 mg combination
3 (Gabaneuron NT™). Average age of the patients was
2 43.47 years and mean weight was 65.21 kg. Physical
0.94 examination like temperature, pulse rate, respiratory rate
1
and blood pressure were within normal limits at baseline.
0
Baseline Week 2 Week 4
As per the data, there was significant improvement in
Duration of treatment symptoms like fatigue, pain in lower legs, weakness,
numbness, tingling, burning pain, severe pain in low back
region. Improvement in symptoms was reflected in
improvement in efficacy parameters- mean pain intensity
Figure 4: Mean general activity score. score, mean general activity score, mood score and sleep
score. Mean pain intensity score (as shown in the figure 3)
Combination therapy decreases pain as well as sleep decreased from 6.57 to 1.00 on treatment with gabapentin-
interference without elevating the side effects.43 The pain nortriptyline combination for 4 weeks. Mean general
intensity with combination therapy of gabapentin and activity score (Figure 4) significantly reduced from

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 Maladkar MN et al. Int J Res Orthop. 2020 Nov;6(6):1365-1370

baseline 6.26 to 0.94 at the end of 4 weeks. Similarly, treatment with a lidocaine patch. Schmerz (Berlin,
mood score (figure 5) and sleep score (figure 6) also Germany). 2004;18(3):172-8.
decreased from 5.71 to 0.72 and 6.35 to 0.88 respectively 12. Wiffen, Philip J. Antiepileptic drugs for neuropathic
at the end of 4 weeks. pain and fibromyalgia-an overview of Cochrane
reviews. Cochrane Database Syst Rev.
The treatment was found to be well-tolerated; 3.6% 2013;11(11):CD010567.
patients experienced adverse events including nausea, 13. Raison VMCL. Neurobiology of depression,
vomiting and drowsiness and most of these events resolved fibromyalgia and neuropathic pain. Frontiers in
without any intervention. Bioscience 14. 2009;5291-338.
14. Taylor, Charles P. Mechanisms of analgesia by
CONCLUSION gabapentin and pregabalin–Calcium channel α2‐δ
[Cavα2‐δ] ligands. Pain. 2009;142(1-2):13-6.
Uncontrolled neuropathic pain has debilitating outcomes 15. Pop-Busui R, Boulton AJ, Feldman EL. Diabetic
with significant negative impact on the quality of life. Neuropathy: A Position Statement by the American
Clinical trials have demonstrated enhanced pain relief with Diabetes Association. Diabetes Care.
combination therapy than with either drug alone. 2017;40(1):136-54.
Gabapentin with nortriptyline seems a potential 16. Handelsman Y, Bloomgarden ZT, Grunberger G,
therapeutic approach in management of uncontrolled Umpierrez G, Zimmerman RS, Bailey TS, et al.
neuropathic pain. This fixed dose combination can American Association of Clinical Endocrinologists
improve treatment adherence, especially in Indian settings and American College of Endocrinology— clinical
where compliance to therapy is generally poor. practice guidelines for developing a diabetes mellitus
comprehensive care plan—2015. Endocr Pract.
Funding: No funding sources 2015;21(1):1-87.
Conflict of interest: None declared 17. Bril V, England J, Franklin GM, Backonja M, Cohen
Ethical approval: Not required J, Del Toro D, et al. Evidence based guideline:
treatment of painful diabetic neuropathy: report of
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methylcobalamin in patients with diabetic CM, Bajaj RK. A step closer in the management of
neuropathy in a randomized, comparative trial. uncontrolled neuropathic pain: gabapentin-
Journal of Diabetes mellitus. 2013;3:22-26. nortriptyline combination. Int J Res Orthop
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tramadol/acetaminophen versus placebo in painful

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