Role of duloxetine in neuropathic pain: A clinical impact, mechanism, challenges in formulation development to safety concern

 

Linu Dash¹, Bimlesh Kumar¹*, Anupriya¹, Varimadugu Bhanukirankumar Reddy¹,

Indu Melkani¹, Narendra Kumar Pandey¹, Kardam Joshi², Dhara Patel²

¹School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, India.

²Topicals Research and Development, Amneal Pharmaceuticals, Piscataway, New Jersey, USA.

 

ABSTRACT:

Neuropathic pain (NP) is a dreadful disease of the somatosensory nervous system with many etiologies. The antidepressant drug is recommended as the first-line drug for the management of such pain. Duloxetine (DXH) is one of the classes of antidepressant drugs having an efficient use in mild to severe pain management. There are many clinical studies conducted on DXH and tested for its effectiveness in NP. For this review articles were collected from PubMed, Science Direct, goggle scholar, and other relevant sites. This review is based on the recently updated articles on duloxetine. The inclusion criteria for this was an English, clinical study with a year of publication between mostly 2010-2020, the DXH and its treatment of NP, comparison of DXH with another drug for the treatment of NP. The only exclusion criteria for this review is the preclinical study. The study design (randomized, cross-sectional, double-blinded), compound DXH regime, outcome measure of the study, and the efficacy were taken into consideration. The present review focused on the molecular targets, challenges, formulation development, comparison with some other drugs in terms of therapeutic benefits, and tolerance with the safety issue of DXH. It was found that DXH provides impactful relief from pain but still modification in the treatment strategies for NP is required.

 

 

 

INTRODUCTION:

Neuropathic pain (NP) is becoming a global burden disease ¹ due to its multifactorial reasons. It is defined as the pain which occurs due to injury in the nerve or any diseases affecting the somatosensory system. The International Association for the Study of Pain (IASP) has a group named the NP Special Interest group (NeuPSIG). In the year 2015 NeuPSIG develop a guideline for the treatment approach toward the NP ^2,3. But there was an exception in this guideline concerning trigeminal neuralgia and for this, a separate guideline is available⁴. Wide varieties of etiological factors are responsible for the development of NP like spinal nerve cord injury, stroke, diabetic neuropathy, multiple sclerosis, peripheral neuropathies, traumatic nerve injury, and postherpetic neuralgia⁵.

 

There are various clinical signs and symptoms of NP that help to diagnosis the kind of pain the person suffering and further respective treatment given to the patients  ^6,7. Hence, treatment of such pain is more challenging. In the last few decades, various therapeutic approaches toward the NP was examined ^{8 9}. NP is an important challenge and many existing treatment strategies are refractory in some patients ^10-13. Because of this GRADE (Grading of Recommendations Assessment, Development, and Evaluation) is strongly recommended ⁹. Majorly all the tricyclic antidepressants (TCAs), Selective serotonin reuptake inhibitors (SSRIs), and Serotonin and norepinephrine reuptake inhibitors (SNRIs) show the action for the treatment of NP. The TCA class of drug act by inhibiting the monoamine oxidase and by blocking the sodium channel ¹⁴. SSRIs show their action by inhibiting the reuptake process of serotonin. But the SNRIs act by inhibiting the reuptake process of both the neurotransmitters serotonin and noradrenaline^9. But still, there is certain kind of challenges associated with the compatibility, compliance and combination therapy. So, Duloxetine (DXH) can be a better choice for the treatment of NP. Chemically DXH is named as LY248686; (+) -N-methyl3-(1-naphthalenyloxy) -2 thiophenepropanamine ¹⁵ . DXH got approval for its use as an antidepressant in 2001 from the Food and Drug Administration (FDA). At that time the property of these drugs to treat the analgesic effect was hidden. In passing years various clinical studies were conducted when shows its treatment of NP^16. If we will see virtually anti-depressant drug has no antinociceptive effect. But still, they are the first-line medication for the management of NP ^17,18. In this review, we will draw attention to the treatment of NP by DXH. Different clinical aspect of DXH was studied for the treatment of NP. It also includes the comparison of DXH with another drug like gabapentin, venlafaxine, pregabalin in a different syndrome of NP to know whether DXH is more or less effective than these drugs. The various neuropathic syndromes which we have reported are NP (NP) due to cancer, acute burn pain, NP due to lung cancer, chemotherapy-induced pain, etc. Finally, we will see some of the challenges associated with DXH and step to overcome those challenges. Hence at the end of this review, we will able to give a complete point of view with clinical evidence for the use of DXH for the treatment of NP.

 

DXH: A SNRIS FOR NP:

DXH is selected for this study because some clinical studies and meta-analyses explored that SNRIs may be more effective than SSRIs in ameliorating depressive symptoms in some circumstances as well as achieving greater remission rates ^19. It is well preferred in 2^nd line use after poor initial treatment response ^19. More balanced affinity for both serotonin and norepinephrine transporter ²⁰. For peripheral diabetic neuropathic pain and fibromyalgia ^19-21. Clinically efficacious for patients of persistent/chronic pain and pre-clinically effective in formalin, capsaicin models, PSNL and L5/L6 SNL ²² and due to its dual inhibition, improved efficacy, tolerability, safety, faster recovery, fewer side effects, and low affinity for other neuronal receptors ²³. There are many drugs like venlafaxine, DXH, milnacipran, desvenlafaxine was studied under SNRI ¹⁵. SNRIs are suggested for NP based on the value obtained in the number needed to treat the NNT index ^24. The NNT was an index that was helpful to compare the effectiveness based on the clinical study conducted. NNT is calculated as 50% of the patient having relief from the pain²⁵. It was found that the number needed to treat NNT value for TCA is 2.1 while Noradrenaline reuptake inhibitor and SNRI have 2.5 and 5.0 respectively ²⁶. Hence, it can be stated that SNRI was having a better analgesic property as compared to other classes of drugs. It is currently the second most commonly prescribed antidepressant with 14.4 million prescriptions written in 2008 alone ^27. The role of DXH evinced in pain generated in urinary incontinence, different symptoms of depression ^28,29, NP with diabetic polyneuropathy ^23,29,30, fibromyalgia ^22,31, and peripheral neuropathy caused by certain anticancer drugs ^20,21,32-38. DXH has a more balanced affinity for both serotonin and norepinephrine transporters ¹⁹, major depressive disorder ³³. Its treatment lacks effects on increases heart rate ³⁹. DXH has little effect on blood pressure or weight ³⁹. Its treatment along with metoprolol results in 3.38 folds significant increase in the area under the curve of Metoprolol and 3.4 fold increase in T_1/2 of metoprolol ⁴⁰.

 

Pharmacokinetic and Pharmacology of Dxh:

Chemically DXH is named N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine. There is no superimposition of its mirror image called a chiral compound. It is formed by the mixture of two chemicals named as (S) -3- chloro-1-(2-thienyl) -1-propanol and its corresponding (R) -butanoate^41,42.  DXH acts by inhibiting the reuptake process of serotonin and norepinephrine having a Ki value of 0.8 and 7.5 nm ⁴³. Due to this inhibition process, the serotonin and norepinephrine level gradually increase in the synaptic cleft and the function of the serotonergic and noradrenergic activity increase in the CNS which helps to reduce NP and depression. It has no affinity to the dopamine receptor. There is also very little affinity of DXH toward the neural receptor-like muscarine, adrenergic, dopamine receptor. Due to this property of DXH exhibit fewer adverse effect ⁴⁴.  A huge number of preclinical studies were conducted to know the exact mechanism behind DXH. A clinical study showed the role of DXH in humans also⁴⁵. In one of the studies, healthy human volunteers were given DXH and observed that the level of serotonin in the blood decrease because due to inhibition of the reuptake mechanism there is no accumulation of serotonin in platelets. It was also reported that the level of catecholamine in plasma as well as in urine changed which is because of the decrease in the reuptake of norepinephrine ⁴⁶. DXH was mostly given in an enteric-coated form because of its acid-labile nature. At a dose between 20-120 mg, it was found that DXH was well absorbed. Some pharmacokinetic properties are given in Table 1 ^44,47. It passes through the hepatic metabolism with the help of two enzymes known as CYP2D6 and CYP1A2. The formed metabolite glucuronide conjugate of 4-hydroxy DXH (47%) and a sulfate conjugate of 5-hydroxy-6-methoxy DXH (22%) is formed which is pharmacologically inactive ⁴⁸. DXH was excreted from the body through urine. Very less that is less than 1 % of DXH was passed unchanged through urine. 70% of metabolized DXH get excreted through urine and the rest 20% by feces ⁴⁸.

 

Table-1: Pharmacokinetic property of DXH

Peak concentration	6-10 h
clearance	101L/h
Half-life	12h
Volume of distribution	1640L
Bind to human plasma protein	96%
Bioavailability	50%

 

But apart from this, DXH was found to have a good clinical aspect for the treatment of NP as it was also found that DXH down-regulates the pathway of TNFα-NFκB. Hence the immunotherapy, which was against TNFα and TLR2 gives relief from allodynia ⁴⁹.

 

Molecular Mechanism of DXH:

DXH act by inhibiting the reuptake process of serotonin (5-HT) and noradrenaline (NA) by which the level of 5-HT and NA increases in the synaptic cleft ⁵⁰. Two different mechanisms take place to show the analgesic efficacy ⁵¹.

 

Role of NA:

The presence of NA in the synaptic cleft act mainly on an α2-adrenergic receptor found on the dorsal horn in the spinal cord. It acts by presynaptic and postsynaptic mechanisms. In the pre-synaptic mechanism, the α2-adrenergic receptor gets bound to the inhibitory G protein ^52,53. It is followed by inhibition of the release of the excitatory neurotransmitter which possesses an analgesic effect. It is found to be effective against allodynia and hyperalgesia in NP because of activation of the α2-adrenergic receptor. In the postsynaptic mechanism due to bind to G protein the potassium channel open. As a result, excitability was decreased and the cell membrane is hyperpolarized. Hence, by the above mechanism, it was concluded that the NA inhibits the NP⁵⁴. The mechanism of NA was depicted in fig 1(a).

 

Role of 5-HT:

Due to inhibition of the reuptake process 5-HT increases in the synaptic cleft as NA. 5-HT shows the potency to modulate the pain as it is also found in the dorsal horn of the spinal cord. The inhibitory (5-HT_1A), as well as excitatory (5-HT2A,2B, 5-HT3, and 5-HT7), were found which come up with nociceptive action. When the pain reaches our brain there is a mobilization of the descending inhibitory system and periaqueductal gray (PAG) gets activated. The rostroventromedial medulla (RVM) gets controlled by the PAG and fiber is projected to the dorsal horn of the spinal cord by which the pain is modified^55,56. As the level of 5-HT increases in the synaptic cleft, there is the activation of the 5-HT receptor which is present in the dorsal horn of the spinal cord. As they get activated, they bind to the G protein-coupled and 5-HT 3A and 5-HT7A receptors produce GABA which produces an analgesic effect. The 5-HT1A, 5-HT2A, and 5-HT2B receptors produce anti-nociceptive action⁵⁷. The mechanism is described in figure 1(b).

 

Fig 1: a: mechanism of NA depicting analgesic property, b:

 

Fig 2: mechanism of 5-HT depicting the analgesic property

 

Challenges of Dxh and Formulation Development:

Every medication poses some challenges. In some case, it is too high and in other, it is much less. DXH also possess some challenge^58,59. The major challenge with DXH is its bioavailability. The oral bioavailability range from 50-80%, which is mostly because of its high process of metabolism in the liver⁶⁰ In a pharmacokinetic study it was also reported that as it is an acid labial substance, it degraded in high acidic pH⁶¹. To overcome the challenge of acid-labile properties it was always available in the enteric-coated form of capsule⁶². In recent years, to overcome the aforementioned challenges of DXH the approaches have been adopted like Solid lipid nano delivery system to protect and control the delivery ²³, Microspheres (using chitosan as carrier and glutaraldehyde as a cross-linking agent) to release the drug in small intestine ⁶³, Mesoporous silica nanoparticles for higher drug loading, greater pH sensitivity, and prolonged sustained release ³⁵, Buccal patches to improve the drug bioavailability by bypassing the hepatic metabolism and acid degradation in the Stomach ⁶⁴, Buccal mucoadhesive films for improving the Bioavailability ⁶⁵ and self nano emulsifying delivery system (SNEEDS or solid-SNEDDS) for solving all pharmaceutical challenges ^66-70. In various conducted clinical trials the starting dose is 40mg per day which is again titrated if necessary⁷¹. But this medication should always be advised after a proper meal to avoid the symptom of nausea and vomiting⁷². Another issue that arises is its high cost and less availability. In that case, the clinician can prescribe another drug like pregabalin or venlafaxine but if the still patient is not responding to these drugs DXH is used to recommend even if the cost is high. The side effect associated with DXH was less as compared to others ⁷³. To overcome this challenge if a person needs immediate medication to get relief from pain then the pain controlling drug-like TCA, NSAID can be given for starting 1 week. After that, it should be discontinued and the DXH can be prescribed for a rest day. Before the clinician prescribed a medication, it is important to know its contra-indication nature. DXH should not be prescribed to a patient who is already in a state of depression and having NP. In that case it might increase the depression by enhancing the anti-nociceptive effect. It was avoided in the progressive paralysis patient. The person already enrolled in a medication of MAO inhibiting drug or tramadol was not advised to prescribe DXH⁷⁴. The patient is contraindicated to DXH who is suffering from hepatic disorder and cardiac disease. By keeping these contraindications in mind DXH can be prescribed as a treatment for NP ⁷⁵. DXH is sold under the brand name Cymbalta⁷⁶. The capsule was the only available form of DXH. It was in the form of an enteric-coated because of its acid-labile nature ⁷⁷ The bioavailability of DXH was around 50%. Hence, to increase the bioavailability different nanoformulation was designed. In one of the studies, S-SNEDDS was formulated and enhancement of the oral bioavailability was observed ⁷⁰. The mesoporous silica nanoparticle (MSNs) acts as a carrier for DXH which was designed to decrease its degradation action due to acid-labile property³⁵. This formulation shows a better pH-sensitive release process. Although there are many nanoformulations of DXH which indicates increased bioavailability, protect from degradation⁴⁷. But till now very few clinical studies were done by taking nanoformulation as a dosage form of DXH. In table 2 different formulation of duloxetine was shown whose main focus is to improve the bioavailability.

 

Table 2: Different formulation of DXH

Formulation of DXH	Method of preparation	Result	Ref
S-Snedds	Physical mixture	To increase the bioavailability and prevent NP	70
Buccoadhesive film	Solvent casting method	To increase the bioavailability and stability of the formulation	65
Mucoadhesive buccal patches	Solvent casting technique	Improve bioavailability by eliminating the fast pass metabolism.	78
Enteric coated delayed release	Fluidized bed coater	Stability is enhanced	79
Proniosomes (thiomer gel)	Coacervation phase separation	Increase in bioavailability, retention time and delivered by olfactory system	80
Mesoporous silica	Sol-gel and solvothermal	It is a better pH Sensitive release (DXH is an acid labile drug)	35
Liquisolid pallet	Extrusion-spheronization	Increase bioavailability	81
DXH loaded micro emulsion	Analytical method	Increase the bioavailability by 1.8 times	82
DXH gel	Cold dispersion	Reduction in neuropathic pain occurs as in oral DXH.	83
Solid lipid nanoparticle	Solid diffusion, ultrasound dispersion	Increase the chemical stability and efficacy	23
SNEDDS	RP-HPLC	To quantify the DXH release during dissolution	84

 

Clinical Evidence of DXH for NP:

The use of DXH in NP was evaluated in 13 clinical trials conducted between 2010-2020.

 

Diabetic NP:

DXH was used found to be useful for the treatment of diabetic NP. It also gets approval for use as diabetic NP in the European Union and the United States. Yan Gao has conducted a study on 215 Chinese patients. The study was designed as randomized, double-blind, and placebo control. The dose of DXH varies from 60-120mg/day (a high dose was given by titration and by seeing the clinical response). Out of 215 patients, 82.1% of patients were grouped under the DXH group and the rest under the placebo group. The observation was made in 12 weeks. At the end of 1, 2, and 4 weeks the response of both the group was noted. It was seen that the DXH group shows a reduction in pain as compared to the placebo control group. In the year 2012, another study was conducted which show the effect of DXH in diabetic NP⁸⁵. It was a double-blind placebo control study having 1139 patients enrolled in it for 12 weeks. A daily dose of 20-120mg/day (titrated as per the response and tolerability) was administered and the response was noted at the end of 12 weeks. It was observed that at the end of 12 weeks there was a decrease in pain in the DXH group. In the year 2015, two clinical studies were conducted by taking DXH as a drug for treatment for diabetic NP^71,86.

 

Central NP caused by spinal cord injury and stroke:

In 2011 a clinical study was conducted by taking the drug DXH for the treatment of central NP which was caused by spinal nerve cord injury and stroke⁸⁷. The randomized and double-blind design was made for the study. The author has enrolled 48 patients out of which two patients were removed during the randomization process before the start of medication. The DXH group receives a dose of 60-120mg/day (the dose was titrated by observing the response and the tolerability). The duration of the study was for 8 weeks.. It was reported that at the end of 8 weeks there was a decrease in the mean score of a pain having a p-value of 0.056. It was also observed that DXH also helps to decrease the dynamic and cold allodynia in these patients.

 

Oxaliplatin-Induced NP:

This is a clinical study that aims to see the efficacy of DXH in chronic oxaliplatin-induced NP ⁸⁸. The design of the study is an open-label pilot study having 39 patients enrolled and it was conducted for 12 weeks. A dose of 30-60mg/day was received by the patient. Before the end of the study 9 patients withdraw from the study due to an adverse event. It was reported that 63.3% of patients (19 patients) have an increase in the score of VAS. It was also observed that the DXH treatment does not affect the liver and renal function and also it has no interference with the chemotherapy. Hence it can be concluded that DXH can be given in this case with a feasible dose of 60mg/day.

 

Chemotherapy-induced NP:

Smith performs a clinical study to determine the treatment of DXH of painful chemotherapy-induced neuropathy pain ²¹. This is a double-blind, randomized, placebo-control study having 231 enrolled patients with few inclusion and exclusion criteria. This is a 5-week study and a dose of 30-60mg/day was given to the patient. Initially, at first week 30mg/day was administered and 60mg/day for the upcoming 4 weeks. At the end of the study, the severity of pain was evaluated by a brief pain inventory short form item. It was reported that there was a reduction in average pain of DXH group (0.34) and placebo group (1.06).

 

NP-Multiple sclerosis (NP-MS):

Multiple sclerosis patients was often found to be reporting about the NP. A study was conducted in the year of 2013 in which the DXH drug was used for the management of NP-MS ⁸⁹. It is a randomized, double-blind placebo control study. This clinical trial involves 239 patients having NP-MS given a dose of 30-120mg/day. But at a first-week dose start with 30mg/day. At the end of the study, average pain intensity (API) was measured for both the group. It was found that DXH group has better improvement in the API. It can be said that DXH possesses analgesic action for the treatment of NP-MS with limited side effect.

 

Cancer Neuropathic Pain (CNP):

Hiromichi Matsuko conducted a clinical trial whose purpose is to predict the response of DXH in the CNP patient⁹⁰. The study design was a multicentric, randomized, and double-blinded, placebo-control study. It involves two parallel-group studies. 20mg of DXH was given orally to the DXH group of patients and after 3 days the observation was noted. If no pain or subsequent pain occurs the same dose was continued otherwise there is an increase in dose of DXH to 40mg for the next 7 days. Out of 70 patients enrolled, one patient withdraws from the study, and two patients were not found eligible for the study. The result was evaluated based on the 5 domains of SF-MPQ-2. It was found that at day 0 the score was more in item 21 and there is a huge difference of score on day 10 (p=0.046). It was reported that the patient under the DXH group experienced a reduction in pain condition, whereas there was an increase in pain in the placebo group. Hence this study state that DXH can effective in a patient who was also not responding to pregabalin. Another pilot study was also conducted in the year 2012 which shows the DXH effectiveness in the neuropathic pain of a cancer patient who was also not responding to the Pragabalin ⁹¹. It includes 15 patients who are having NP and suffering from cancer. 20-40mg/day dose was to be administered to the patient. At the end of the study, 11 patients show effective results and there was also a decrease in the pain (Table.3.).

 

Acute Burn Pain:

This acute burn pain is categorized under both nociceptive pain as well as NP. The main purpose of this study was to show the efficacy of the DXH for the management of acute burn pain and decrease the characteristic of NP ⁹² A 3-week prospective, open-label, randomized control trial study design was made. The sample size was 46. DXH was given orally on 60mg/day after lunch to avoid nausea and vomiting. After 3 weeks the intensity of the background pain and procedural pain was observed by NPS (NP Scale) and VAS (Visual analog scale) respectively. The baseline observation was made. The intensity was found to be 9.13 having P= 1 in both the group. The intensity of NP was found to be 1.74 having the p=0.003 (Table.3.).

 

The postoperative effect after total hip or knee arthroplasty:

This is a clinical study that shows the efficacy of DXH in the postoperative effect after the knee replacement⁹³. The study was a multicentric, open-label study enrolling the patient of knee replacement. A dose of 60mg/day was given to the patient and the primary outcome and secondary outcomes were measured. The primary endpoint was a measure of the degree of postoperative pain after 6 months of operation and the secondary endpoint was evaluated after 12 months. It was found that the pain, problem associated with joint, NP-like symptoms was improving after the treatment with DXH. Another clinical study was also conducted to prove the efficacy of DXH in osteoarthritis knee pain⁹⁴.

 

Table 3: Clinical study of DXH in treatment of NP

NP	Dose (mg/day)	Study design	Duration (Weeks)	Samples	Outcome	Ref
Diabetic	60-120	Placebo control, Double blind Randomized	12	215	Brief Pain Inventory was found to be decreased in the 1,2 and 4 weeks, having	86
	20-120	Double blind, Placebo control	12	1139	A PK/PD model was used for adequate pain relief	85
	40-60	Randomized, Open label study	52	258	The increase in average pain score was -2.1.	71
	60	Placebo control, Parallel, Double blind, Randomized	12	405	The decrease in severity of reduction in pain was found in DXH. Least square mean change for DXH was -2.4	86
Central	60-120	Randomized, placebo control and double blind	8	48	Decrease in the mean score of pain having p value 0.056	87
Oxaliplatin	30-60	Open label, pilot study	12	39	Increase in the score of VAS at the end of 12 weeks.	88
Chemotherapy	30-60	Randomized, double blind, placebo control study	5	231	The average pain score for DXH at the end of the study is 0.34	21
Multiple sclerosis	30-120	Randomized, double blind, placebo control study	18	239	DXH group has better improvement in average pain intensity (API).(DXH: -1.86 Placebo: -1.07)	89
Neuropathic Cancer Pain	20	Multicentric, randomized, double blinded, placebo control	10 days	70	There was a decrease in pain at day 10 then day 0 (P=0.04). Pain scores = 5.6/10	90
	20-40	Pilot study	2-4	15	Duloxetine treat by reducing the pain.	91
Acute burn pain	60	Open label, randomized control trial	3	46	Intensity of pain=1.74 (P= 0.003)	92
Diabetic	30-60	Randomized study	6	30	Less conditioned pain modulation (CPM)	95
Post-operative effect	60	Multicenter, pragmatic, prospective, open-label, randomized controlled trial	10	-	There was increase in relief after postoperative effect (after hip / knee replacement)	93

 

Comparision Study:

The review includes the comparison of DXH with another drug to prove the efficacy of it in the NP as compared to other drugs. The comparison will help the clinician to prescribe the best drug for the NP patient.

 

Duloxetine Vs Pragabalin, Gabapentin and Venlafaxine:

Tannenberg conducted a clinical trial in the year 2011 to show the compare the effect of DXH and pregabalin for the treatment of diabetic NP ⁹⁶. This study was an open-label study conducted for 12 weeks. 407 patients get enrolled in this study and get divided into 3 groups. One group receiving only DXH, the second group receives pregabalin and the last group receives the combination of DXH and gabapentin. A dose of 60mg/day DXH, 300mg/day pregabalin, and more than 900mg/day gabapentin was administered to patients enrolled. It was found that the endpoint of pain score was -2.6 for duloxetine and -2.1 for pregabalin. It was reported that DXH was as good as pregabalin for the treatment of Diabetic induced NP. The dose was also less as compared to pregabalin and gabapentin. Another study was conducted by Tannenberg comparing the DXH vs pregabalin in diabetic neuropathy pain, but this study slightly deviates from the above-mentioned study ⁹⁷. This clinical study subgroup the patient based on using and not using the concomitant antidepressant drug. It is a randomized study enrolled with 407 patients (79 patients with the treatment of antidepressants and the remaining patient without antidepressant medication) for 12 weeks. At the end of the study, it was concluded that the patient suffering from diabetic NP inadequately treated with gabapentin without antidepressant medication show better results when it was switched to DXH.

 

Diabetic polyneuropathy can result in uncontrolled severe pain and sometimes with no pain. In this clinical study, the DXH and gabapentin were used and the comparison was made between the two for the treatment of polyneuropathy⁹⁸. The patient enrolled were between the age of 18 to 75 years. The HbA1c values should be less than 10 and the VAS score was at least 40/100mm. The indication of diabetes must be between 1 to 15 years. The exclusion criteria were patients with liver or kidney dysfunction and alcoholics. The duration of the study was 8 weeks. It is a randomized, double-blind prospective study that has a parallel grouping of A and B. Group A was given the intervention of gabapentin, and group B was given DXH orally at a dose of 60mg per day and if it was found to tolerate, then the dose was increased to 60mg. Similarly, in gabapentin, a dose of 300mg/day is given and it can be increased up to 900mg per day. The VAS, CGIC, Sleep interference score was observed and it was observed that almost both the drug was found to be equally effective for treatment. The observation was recorded at zero-day, the end of 1^st week, 4^th week, and 8^th week. Although there was equal effectiveness of both the drug to treat polyneuropathy there was less side effect associated with DXH. Gabapentin shows a fast response with more side effects. Hence the medication of the DXH group (n=47) was found to be better than the gabapentin (n=41). Hence, through this clinical trial, it was concluded that for preventing the side effect DXH should be prescribed. The only problem which exists in the present study with DXH is its late response. It can also overcome by giving medication of other pain reliving like NSAID, gabapentin in the first week and then shift to DXH by discontinuing the other medication.

 

Chemotherapy possesses a lot of side effects and one of them is chemotherapy-induced peripheral neuropathy (CIPN). In this clinical study, DXH and venlafaxine were used to compare the efficacy for the treatment of CIPN ⁹⁹. It is a double-blinded clinical study having 170 patients enrolled. The duration of the study was for 1 month and observation was taken on every two weeks (day 1, week 2, week 4). The motor, sensory, cranial neuropathy grade was evaluated which is based on the BPI guideline. It was reported that at the first 2 weeks there observed no significant difference in these factors. But there was a slight decrease in blood pressure in the venlafaxine group and no effect on blood pressure was found in the DXH group. In the 4^th week, the reduction was observed in the cranial neuropathic grade, motor, and sensory pain. But there was more reduction in the case of DXH than venlafaxine.

 

DXH in treatment of neuropathic cancer pain (NCP) Vs Opioid and Gabapentin:

Hiromichi Matsuoka performed the first clinical study in which the analgesic effect of DXH was observed in the patient of neuropathic cancer pain who are intolerated by the medication of opioid and gabapentin¹⁰⁰. This study was conducted in 14 sites in Japan. The patient who is taking an opioid or intolerated to gabapentin, having NRS value more than 4 and HADS value less than 20 are selected as the inclusion criteria (Table.4.). The two parallel groups were the design of which one is an intervention group of DXH of dose 20-40mg per day and the other group is placebo control. The duration of this study was 10 days. The NRS, SR-MPQ-2, Opioid consumption, EORTC-QLQ-C15 was taken as the parameter to identify the analgesic effect. The observation was recorded on day 1, day 3^rd, and the 10^th day. It was found that the DXH was found effective for treating neuropathic cancer pain. One similar type of study was also conducted in the year of 2019¹⁰¹. That study also reported that the patient who are intolerated to the opioid or gabapentin, they can be prescribed with DXH because it shows the effective result to reduce the pain. These are the clinical trial, which is conducted on DXH for treatment of various types of NP and published in the last ten years (2010-2020) (Table 4).

 

Table 4: Clinical study of DXH to compare with another drug in the treatment of NP

NP Types	Comparator	DXH (mg/day)	Study design	Duration	Samples	Outcome	Ref
Diabetic	Pragabaline (300mg/day) Gabapentin (>900mg/day)	60	Open label, Randomized	12 weeks	407	The pain score at the endpoint for DXH was -2.6 and for pregabalin -2.1.	96
Diabetic	Gabapentin (300mg/day)	60	Prospective double-blind random	8 weeks	104	Both are equally effective, DXH has fewer side effect than gabapentin	98
CIPN	Venlafaxine (37.5mg)	30	Double-blind study	1 month	170	A decrease in NP was observed more in DXH than venlafaxine (P<0.05)	99
NCP	-	20	Multicentric, prospective, double-blind, randomized, placebo-controlled	10 Days	70	DXH show action against NP in the not respondent to opioid and gabapentin.	100
NCP	-	20-40	A multicentric randomized double-blind placebo-controlled trial	10 Days	70	BPI-Item 5 value was recorded to be 4.03 for DXH group (P=0.046).	101
Lung Cancer Patient	Pragabaline (300mg/day)	60	Prospective, Randomize, Open label Study	3 Months	44	The significant difference of LANNS was found more in DXH than pregabalin (p=0.001)	102
Diabetic	Pragabaline (600mg/day), Amitriptyline	60	Randomize, double-blind, parallel study	35 days	104	The three of the drug shows equal response for NP	103

NCP: Neuropathic Cancer Pain, CINP: Chemotherapy Induced NP, Neuropathic Pain: NP

 

Tolerance and Safety of DXH:

DXH (brand name Cymbalta) is well tolerated at a dose of range 30-120mg per day. The adverse reaction was found and is most common like dry mouth, constipation, nausea. But this reaction was found only at the start of the treatment ¹⁰⁴. When the treatment persists and continues for some time the adverse reaction get disappeared ^105,106. But the medication of DXH for a long period (6 months -1 year) result in an adverse reaction which was reported in the adult patient ¹⁰⁷. The adverse reaction is vertigo, blurred vision, and palpitation¹⁰⁸. In much clinical analysis, it was reported that DXH to not harm our cardiovascular system. It has a modest effect on our blood pressure and heart rate and no effect on the electrocardiogram¹⁰⁹. In the year of 2014, a clinical study was conducted to prove the efficacy of DXH, pregabalin, and gabapentin and the result shows that DXH was found to be safe in diabetic-induced NP ¹¹⁰. A clinical trial was also conducted to show the efficacy, safety of DXH in the osteoarthritis of the knee ¹¹¹. DXH has neither increase nor decrease the risk of suicide or any aggressive behavior. But the risk involved with DXH increases in the case of concomitant medication. DXH was prescribed after a meal to avoid nausea and vomiting side effect. A cohort observation study was conducted on web – based intensive monitoring. In 368 patients get registered and reported the adverse event. They take DXH for 6 months. The person suffering from diabetic neuropathy when administered with DXH, there might be a slight change in blood glucose level, but this change can be manageable¹¹² and considered as safe ¹¹³. There was no harm to the hepatic function in body when DXH was administered ¹¹⁴.

 

CONCLUSION:

The treatment for NP is still a major issue. NP occurs in many diseases like a cancer patient, burn patients, etc. Mostly this pain was observed in the patient receiving the chemotherapy treatment. The recommended first-line medication for NP is an antidepressant drug. Both the TCA and SNRI classes of an antidepressant can be used as a treatment therapy for pain management. In this, we have enlightened the study by use of DXH in the treatment of various types of NP. DXH is double edge blade. The contraindication of DXH should be kept under consideration while prescribing the DXH.

 

Terms Used for Clinical Evaluation of Pain:

BPI-SF Item 5: A tool used to measure the average pain severity from 0 to 10 point scale (0= less pain), SF-MPQ-2: A tool used to study different effect due to the pain mechanism, ADS: Used for measurement of psychiatric symptoms (anxiety or depression), PCS: Used to measure the severity of cancer related pain , NPS: Tool used for the assessment of NP condition, VAS: It is a tool used for evaluation of procedural pain, EORTC- QLQ-C15-PAL: Used for evaluation of quality of patient life, LANSS: It is a questionnaire form filled by patient

 

ABBREVIATION:

IASP: International Association for the Study of Pain, NeuPSIG: Neuropathic pain Special Interest group, GRADE: Grading of Recommendations Assessment, Development, and Evaluation, SNRI: Selective serotonine and nor norepinephrine reuptake Inhibitor, TCA: Tricyclic antidepressant, NNT: Number needed to treat, 5-HT: Serotonine, NA: Noradrenaline, PAG: Periaqueductal gray, RVM: Rostroventromedial medulla, NPS: NP Scale, VAS: Visual analog scale, CIPN: Chemotherapy induced peripheral neuropathy, NCP: Neuropathic cancer pain, BPI-SF: Brief Pain Inhibitory- Short Form, SF-MPQ-2: Short form McGill Pain Questionnaire 2, HADS: Hospital Anxiety and depression scale, PCS: Pain Catastrophizing scale, NPS: Neuropathic pain scale, VAS: Visual analogue scale, LANSS: Leeds Assessment Of neuropathic symptoms and signs, Duloxetine: DXH.

 

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Accepted on 09.03.2022               © RJPT All right reserved

Research J. Pharm.and Tech 2022; 15(4):1852-1862.