CPQ Medicine (2021) 12:4Cohort Study
Diabetes Neuropathic Pain: Therapeutic Agents for the Ailment and
Analytical Methods for the Measurement of Their Biological Fluids
Chika Mbah, J.
Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of
Nigeria, Nsukka, Enugu State, Nigeria
*Correspondence to: Dr. Chika Mbah, J., Department of Pharmaceutical and Medicinal Chemistry,
Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria.
Copyright © 2021 Dr. Chika Mbah, J. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 06 September 2021
Published: 21 September 2021
Keywords: Diabetes Neuropathic Pain; Therapeutic Agents; Biological Fluids; Analytical Methods
Diabetic neuropathy consists mainly of two types namely, sensorimotor and autonomic neuropathy
respectvely. Pain, paraesthesia and sensory loss are common features of sensorimotor neuropathy
while malignant arrhythmia, myocardial infarction and sudden death are associated with autonomic
neuropathy. The aim of the study was to provide analytical methods employed to measure therapeutic
agents utilized in the treatment of diabetes neuropathic pain in biological fluids. The methodology
involved obtaining relevant information from scientific journals, reference books in libraries and
internet websites. The results indicate that treatment of the ailment mostly involve the use of
antiepileptic agents, antidepressants, antihypertensive agents, opioid analgesic agents. Gas or liquid
chromatographic methods (hyphenated and non-hyphenated) electrochemical, electrophoresis and
spectroscopic methods were found to be the analytical methods used to measure therapeutic agents
for diabetes neuropathic pain in biological fluids. Of all these analytical methods, high performance
liquid chromatography (liquid chromatographic method) seems to be the analytical method of
Diabetes mellitus a clinical syndrome characterized by an increase in plasma blood glucose.
Diabetes neuropathy is a peripheral nerve dysfunction or damage associated diabetes mellitus. Neuropathic
pain is a complex phenomenon that is characterized by burning pain as well as allodynia and hyperalgesia
involving both the peripheral and central nervous systems.
Diabetes neuropathy is generally classified into:
1. Diffuse neuropathy: consists of (a) distal symmetric polyneuropathy (DSPN), typical example is mixed
small and large-fiber neuropathy; (b) autonomic, typical example is cardiovascular autonomic neuropathy
(CAN); (c) gastrointestinal, typical example is gastropathy (diabetic gastroparesis); (d) urogenital, typical
example is neurogenic bladder (diabetic cystopathy); (e) distal hypohydrosis/anhidrosis, typical example is
2. Mononeuropathy (mononeuritis multiplex)-consists of focal neuropathy, typical examples are cranial
neuropathies and focal limb neuropathies.
3. Polyradiculopathy or radiculopathy- consists of multifocal neuropathy, typical examples are thoracolumbar
radiculoneuropathy and lumbosacral radiculoplexus neuropathy (Bruns-Garland syndrome) [1,2].
The causes of the diabetes neuropathy include hyperglycaemia (resulting in over-activity of polyol pathway
through aldose reductase); increase in oxidative stress (leading to increased lipid peroxidation); alteration
of fatty acid metabolism (resulting in depletion of γ linolenic acid and PGE1- prostaglandin precursors);
decrease in nerve growth factors concentration (namely glial derived neurotrophic factor, ciliary neurotrophic
factor, insulin-like growth factors) and inflammatory change in the nerve [3,4].
Diabetes neuropathy is associated with symptoms such as rapid progression of limb weakness, absent ankle
reflexes, retinopathy, foot deformity or ulcer, callus, severe and deep aching pain (abnormal discharges from
diseased somatosensory neurons are considered to be responsible); weakness (follows the pain that afflicts
proximal, but occasional for distal muscles); weight loss etc. [5,6]. These symptoms are generally worse at
night leading to sleep disturbance and with painful symptoms during the day, the patient ability to carry out
daily activities is diminished [7,8].
The diagnosis of the disease involves assessment of muscle power, pinprick sensation test (small-fiber
function), vibration sensation test (large-fiber function), temperature perception test (using object of 10 to
40ºC), and joint position test. Other tests may involve skin biopsy for assessing neuropathies with distal loss
of unmyelinated nerve fibers, cardiovascular autonomic reflex tests for heart rate responses to deep breathing
and standing, blood pressure response to standing, objective gastric emptying test and complete urodynamic
The management of diabetic neuropathy will involve:
Screening for symptoms and signs of diabetic neuropathy is very vital, because it assists clinicians to detect
the earliest stages of neuropathy. The practice will bring about early intervention by optimizing glucose
control and other risk factors, that might contribute to the disease state [12,13].
(ii) Treatment with therapeutic agents:
Pain control is the mainstay of treatment of the disease. However, physiotherapy can offer assistance in more
severe cases. Therapeutic agents that have shown efficacy in the treatment of pain associated with the disease
1. Amitriptyline: derivative of tricyclic tertiary amine. Chemically defined as 5-(3-dimethylaminopropyliden)-
10,11-dihydrodibenzcyclo-heptene. It acts by inhibiting 5-hydroxytryptamine (5-HT) and norepinephrine
reuptakes; enhances norepinephrine and 5-HT neurotransmission; promotes low clearance of norepinephrine
and 5-HT from the synapse [14,15]. Recommended dose is 150-300mg daily
2. Carbamazepine: derivative of iminostilbene. Chemically defined as benzo[b]benzazepine-11-
carboxamide. It acts by binding to voltage-dependent sodium channels hence inhibiting spontaneous activity
in regenerating small-calibre primary afferent nerve fibers [16,17] Recommended dose is 100-800mg daily.
3. Desipramine: derivative of tricyclic secondary amine. Chemically defined as 3-(10,11-dihydro-5Hdibenzo[
b,f]azepin-5-yl)-N-methylpropan-1-amine..Its mechanism of action is similar to amitriptyline
[18,19]. Recommended dose is 150-300mg daily.
4. Duloxetine: is a derivative of thiophenepropylamine. Chemically defined as (+) - (S) - N-methyl - γ-
(1- naphthyloxy) -2-thiophenepropylamine. It acts as a selective norepinephrine and serotonin reuptake
inhibitor [20,21]. The recommended dose is 60-120 mg daily.
5. Gabapentin: derivative of a γ-aminobutyric acid. It is chemically defined as 1-(aminomethyl)
cyclohexaneacetic acid. Its mechanism of action is similar to pregabalin [22,23]. Recommended dose is
6. Irbesartan: derivative of biphenyl tetrazole. Chemically defined as as 2-n-Butyl-4-spirocyclopentane-1-
[(2’-tetrazol-5-yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. A potent long- acting AII receptor antagonist
with high specificity for the AT1 subtype and acts by inhibiting angiotensin II binding to the AT I receptor
[24,25]. Recommended dose is150-300mg daily
7. Nortriptyline: derivative of tricyclic secondary amine. Chemically defined as 5-(3-methylaminopropyliden)-
10,11-dihydrodibenzcyclo-heptene Its mechanism of action is similar to amitriptyline [26,27]. Recommended
dose is 50-150mg daily
8. Pregabalin: is a derivative of gamma-amino butyric acid. It is chemically defined as (3S)-3-(aminomethyl)-
5-methylhexanoic acid. It acts by binding with high affinity to the alpha-2-delta protein subunit of
voltage-gated calcium channel thereby reducing the release of neurotransmitters, including the excitatory neurotransmitter l-glutamate [28,29]. The inhibition of glutamatergic transmission is elicited in the spinal
cord by direct activation of protein kinase C or nociceptive stimulation. Recommended dose is 150-
9. Tapentadol: derivative of phenol propylamine. Chemically, is defined as 3-[(1R, 2R)-3-(dimethylamino)-
1-ethyl-2-methylpropyl] phenol. It acts through m-opioid receptor agonism and noradrenaline reuptake
inhibition. It is a centrally acting opioid analgesic [30,31]. Recommended dose is 50-100mg daily
10. Tramadol: derivative of phenylcyclohexanol. Chemically is (IRS,2RS)-2-[(Dimethylamino)methyl]-1-
(3-methoxyphenyl)cyclohexanol. It acts as a weak m-opioid receptor agonist, norepinerphrine and serotonin
reuptake antagonist [32,33]. Recommended dose is 50-100mg daily
11. Venlafaxine: derivative of bicyclic phenethylamine. Chemically it is defined as1-[2-(dimethylamino)-1-
(4-methoxyphenyl) ethyl] cyclohexanol. It acts a selective norepinephrine and serotonin reuptake inhibitor,
however, to a lesser extent, dopamine reuptake in the central nervous system [34,35]. Recommended dose
Other drugs of interest for patients whose pain is resistant to the above drugs are mexiletene, citalopram,
paroxetine, lamotrigine, topiramate, pethidine, morphine.
To avoid adverse or side effects associated with therapeutic agents as well as inability to produce the required
therapeutic responses, monitoring of their plasma concentration levels becomes very important. To achieve
the monitoring and determination of plasma drug concentrations analytical methods that are accurate,
precise, sensitive, selective and specific are necessary. Such analytical methods may include chromatographic,
electrochemical and spectroscopic methods. However, chromatographic methods very often are the analytical
methods of interest due their sensitivity and specificity. Chromatographic methods, namely high (or ultra)
performance liquid chromatography and gas chromatography are mostly utilized either as hyphenated or
non-hyphenated system. Hyphenation is an on-line combination of a chromatographic technique and one
or more spectroscopic detection techniques.
Biological fluids are very important to life because they assist in the maintenance of body homeostasis. The
fluids mostly analyzed are whole blood, serum or plasma, urine, saliva and cerebrospinal fluid. The present
study provides various analytical methods that have been used to measure therapeutic agents for diabetic
neuropathic pain in human biological fluids.
Biological fluids and analytical methods reported for the following therapeutic agents include:
1. Amitriptyline: determined in: (a) plasma [36-39] by non-hyphenated system,  by hyphenated system,
 by thin-layer chromatographic system (b) serum [42-44] by non-hyphenated system and  by
radioimmunoassay system (c) urine [45-47] by radioimmunoassay system and non-hyphenated system, (d)
saliva  by radioimmunoassay system, (e) human vitreous humor  by non-hyphenated system.
2. Carbamazepine: determined in: (a) plasma [49-52] by non-hyphenated system, (b) serum [53-56] by
non-hyphenated system, [57,58] by hyphenated system and  by spectroscopic system (c) urine  by non-hyphenated system, (d) saliva  by non-hyphenated system and (e) breast milk  by nonhyphenated
3. Duloxetine: determined in: (a) plasma [62,63] by non-hyphenated system, [64-66] by hyphenated system,
(b) serum [67-69] by non-hyphenated system.
4. Desipramine: determined in: (a) plasma [70-73] by non-hyphenated system,  by hyphenated system,
 by thin-layer chromatography (b) serum  by non-hyphenated system,  by hyphenated system
(c) urine  by hyphenated system.
5. Gabapentine: determined in: (a) plasma [77-80] by non-hyphenated system and [81-83] by hyphenated
system,  by capillary electrophoresis (b) serum [85-89] by non-hyphenated system and [90-92] by
hyphenated system (c) urine [93-95] by non-hyphenated system.
6. Irbesartan: determined in (a) plasma [96-98] by non-hyphenated system [99-102] by hyphenated system
(b) serum  by non-hyphenated system, (c) urine  by non-hyphenated system.
7. Nortriptyline: determined in: (a) plasma [36,37,38,105,106] by non-hyphenated system and  by
hyphenated system  by thin-layer chromatography, (b) serum [38,42,44] by non-hyphenated system and
 by hyphenated system,  by radioimmunoassay system (c) urine  by non-hyphenated system,
 by hyphenated system.
8. Pregabalin: determined in: (a) whole blood  by hyphenated system (b) plasma [108,109] by nonhyphenated
system, [110-113] by hyphenated system (c) serum [86,114] by non-hyphenated system (d)
urine  by non-hyphenated system, and  by hyphenated system.
9. Tapentadol: determined in: (a) serum  by non-hyphenated system,  by hyphenated system, (b)
urine [118,119] by hyphenated system, (c) saliva  by hyphenated system.
10. Tramadol: determined in: (a) whole blood  by hyphenated system (b) plasma [121-125] by nonhyphenated
system, [126,127] by hyphenated system, (b) urine  by non-hyphenated system,
11. Venlaflaxine: determined in: (a) whole blood  by hyphenated system (b) plasma [129-131] by nonhyphenated
system and [132-136] by hyphenated system,  by capillary electrophoresis (b) serum 
by non-hyphenated system.
The study has shown that therapeutic monitoring of these therapeutic agents will not be a problem since
several analytical methods exist for their measurement in biological fluids.
Gas and liquid chromatographic (hyphenated or non-hyphenated) methods including capillary
electrophoresis were mostly utilized methods in the analyses of these diabetes neuropathic pain agents.
The chromatographic analytical methods have advantages over electrochemical or spectroscopic methods
in terms selectivity and sensitivity. However, as the chromatographic methods involve use of expensive
and sophisticated equipment analysts in developing and underdeveloped nations, continue to employ
spectroscopic methods as the technique of interest due to their cost effectiveness, simplicity, accuracy and
In order to avoid poor quality of life associated with diabetes neuropathic pain, diagnosis and symptomatic
treatment are very important. Strict glycaemic control is very vital in the prevention of diabetes neuropathy.
The treatment of severe pain associated with the disease involves the use of antidepressants, anticonvulsants,
anti-hypertensive agents, opioid analgesic agents. Finally, although chromatographic methods are the best
and most important methods of choice, electrochemical and spectroscopic methods still find significant
place in the measurement of diabetes neuropathic pain therapeutic agents in biological fluids.
- Albers, J. W. & Pop-Busui, R. (2014). Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep., 14(8), 473-479.
- Llewelyn, G. (2003). The diabetic neuropathies: types, diagnosis and management. J Neurol Neurosurg Psychiatry., 74(Suppl 2), ii15-ii19.
- Zenker, J., Ziegler, D. & Chrast, R. (2013). Novel pathogenic pathways in diabetic neuropathy. Trends Neurosci., 36(8), 439-449.
- Spence, M. C., Potter, J. & Coppini, D. V. (2003). The pathogenesis and management of painful diabetic neuropathy: a review. Diabetic Med., 20(2), 88-98.
- Callaghan, B. C., Cheng, H. T., Stables, C. L., Smith, A. L. & Feldman, E. L. (2012). Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol., 11(6), 521-553.
- Duby, J. J., Campbell, R. K., Setter, S. M., White, J. R. & Rasmussen, K. A. (2004). Diabetic neuropathy: an intensive review. Am J Health Syst Pharm., 61(2), 160-173.
- Boulton, A. J., Vinik, A. I., Arezzo, J. C., Bril, V., Feldman, E. L., Freeman, R., Malik, R. A., Maser, R. E., Sosenko, J. M. & Ziegler, D. (2005). American Diabetes Association Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care, 28, 956-962.
- Tesfaye, S. & Selvarajah, D. (2012). Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev., 28(Suppl 1), 8-14.
- Simmons, Z. & Feldman, E. L. (2002). Update on diabetic neuropathy. Curr Opin Neurol., 15(5), 595-603.
- Cruccu, G., Sommer, C., Anand, P., Attal, N., Baron, R., Garcia-Larrea, L., Haanpaa, M., Jensen, T. S., Serra, J. & Treede, R. D. (2009). EFNS guidelines on neuropathic pain assessment: revised. Eur J Neurol., 17(8), 1010-1018.
- Tesfaye, S., Boulton, A. J., Dyck, P. J., Freeman, R., Horowitz, M., Kempler, P., Lauria, G., et al. (2010). Toronto diabetic neuropathy expert group: Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity and treatment. Diabetes Care, 33(10), 2285-2293.
- Ang, L., Jaiswal, M., Martin, C. & Pop-Busui, R. (2014). Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep., 14(9), 528-517.
- Perkins, B. A., Olaleye, D., Zinman, B. & Bril, V. (2001). Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care, 24(2), 250-256.
- Moore, R. A., Derry, S., Aldington, D., Cole, P. & Wiffen, P. J. (2015). Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev., 2015(7), CD008242.
- Max, M. B., Culnane, M., Schafer, S. C., et al. (1987). Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology, 37(4), 589-596.
- Ambrosio, A. F., Soares-Da-Silva, P., Carvalho, C. M. & Carvalho, A. P. (2002). Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res., 27(1-2),121-130.
- Deli, G., Bosnyak, E., Pusch, G., Komoly, S. & Feher, G. (2013). Diabetic neuropathies: diagnosis and management. Neuroendocrinology, 98(4), 267-280.
- Hearn, L., Moore, R. A., Derry, S., Wiffen, P. J. & Phillips, T. (2014). Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev., 2014(9), CD011003.
- Max, M. B., Lynch, S. A., Muir, J., Shoaf, S. E., Smoller, B. & Dubner, R. (1992). Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med., 326(19), 1250-1256.
- Goldstein, D. J., Lu, Y., Detke, M. J., Lee, T. C. & Iyengar, S. (2005). Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain, 116(1-2), 109-118.
- Raskin, J., Wang, F., Pritchett, Y. L. & Goldstein, D. J. (2006). Duloxetine for patients with diabetic peripheral neuropathic pain: a 6-month open-label safety study. Pain Med., 7(5), 373-385.
- Shimoyama, M., Shimoyama, N. & Hori, Y. (2000). Gabapentine affects glutamatergic excitatory neutrotramission in the rat dorsal horn. Pain, 85(3), 405-414.
- Backonja, M. & Glanzman, R. L. (2003). Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther., 25(1), 81-104.
- Weber, A. (2001). Review of irbesartan in antihypertensive therapy. Comparing with other antihypertensive agents. Current Ther Res., 62, 505-532.
- Gillis, J. C. & Markham, A. (1997). Review of pharmacology and clinical efficacy of irbesartan. Drugs, 54, 885-902.
- Derry, S., Wiffen, P. J., Aldington, D. & Moore, R. A. (2015). Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev., 1(1), CD011209.
- Saarto, T. & Wiffen, P. J. (2007). Antidepressants for neuropathic pain. Cochrane Database Syst Rev., (4), CD005454.
- Blommel, M. L. & Blommel, A. L. (2007). Pregabalin: An antiepileptic agent useful for neuropathic pain. Am J Health-System Pharmacy., 64(14), 1475-1482.
- Rosenstock, J., Tuchman, M., LaMoreaux, L. & Sharma, U. (2004). Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain, 110(3), 628-638.
- Schwartz, S., Etropolski, M., Shapiro, D. Y., et al. (2011). Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin., 27(1), 151-162.
- Vinik, A. I., Shapiro, D. Y., Rauschkolb, C., et al. (2014). A randomized withdrawal, placebo-controlled study evaluating the efficacy and tolerability of tapentadol extended release in patients with chronic painful diabetic peripheral neuropathy. Diabetes Care, 37(8), 2302-2309.
- Harati, Y., Gooch, C., Swenson, M., et al. (1998). Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology, 50(6), 1842-1846.
- Harati, Y., Gooch, C., Swenson, M., et al. (2000). Maintenance of the long-term effectiveness of tramadol in treatment of pain of diabetic neuropathy. J Diabetes Complications., 14(2), 65-70.
- Andrews, J. M., Ninan, P. T. & Nemeroff, C. B. (1996). Venlafaxine: a novel antidepressant that has a dual mechanism of action. Depression, 4(2), 48-56.
- Rowbotham, M. C., Goli, V., Kunz, N. R. & Lei, D. (2004). Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain, 110(3), 697-706.
- Watson, I. D. & Stewart, M. J. (1977). Quantitative determination of amitriptyline and nortriptyline in plasma by high-pressure liquid chromatography. J Chromatogr., 132(1), 155-159.
- Dhar, A. K. & Kutt, H. (1979). An improved gas-liquid chromatographic procedure for the determination of amitriptyline and nortriptyline levels in plasma using nitrogen-sensitive detectors. Ther Drug Monitor., 1(2), 209-216.
- Hartter, S. & Hiemke, C. (1992). Column switching and high-performance liquid chromatography in the analysis of amitriptyline, nor- triptyline and hydroxylated metabolites in human plasma or serum. J. Chromatogr. B., 578(2), 273-282.
- Gifford, L. A., Turner, P. & Pare, C. M. B. (1975). Sensitive method for the routine determination of tricyclic antidepressants in plasma using a specific nitrogen detector. J Chromatogr., 105, 107-113.
- Kudo, K., Litsufuchi, N. & Imamura, T. (1997). Selective determination of amitriptyline and nortriptyline in human plasma by HPLC with ultraviolet and particle beam mass spectrometry. J Anal Toxicol., 21(3), 185-189.
- Faber, D. B., Mulder, C., Mann, T. & Veld, W. A. (1974). A thin-layer method for the determination of amitriptyline and nortriptyline in plasma. J Chromatogr., 100(1), 55-61.
- Jorgensen, A. (1975). A gas chromatographic method for the determination of amitriptyline and nortriptyline in human serum. Acta Pharm Toxicol., 36(1), 79-90.
- Streator J. T., Eichmeier L. S. & Caplis M. E. (1980). Determination of tricyclic antidepressants in serum by high pressure liquid chromatography on a silica column. J. Anal. Toxicol., 4(2), 58-62.
- Connor, J. N., Johnson, G. F. & Solomon, H. M. (1977). Quantitation of amitriptyline and nortriptyline in human serum. J Chromatogr., 143(4), 415-421.
- Mould G. P., Stout, G., Wynneaherne, G, & Marks, V. (1978). Radioimmunoassay of amitriptyline and nortriptyline in body fluids. Ann Clin Biochem., 15(1-6), 221-252.
- Farag, R. S., Darwish, M. Z., Hammad, H. A. & Fathy, W. M. (2013). Validated method for the simultaneous determination of some tricyclic antidepressants in human urine samples by gas chromatography-mass spectrometry. Int J AnaL Bioanal Chem., 3(2), 59-63.
- Farag, R. S. & Ahmed, A. M. (2011). RP-HPLC Determination of amitriptyline hydrochloride in tablet formulations and urine. Asian J. Research Chem., 4(1), 1-7.
- Evenson, M. A. & Engstrand, D. A. (1989). A SepPak HPLC method for tricyclic antidepressant drugs in human vitreous humor. J Anal Toxicol., 13(6), 322-325.
- Oh, E., Ban, E., Woo, J. S. & Kim, C. K. (2006). Analysis of carbamazepine and its active metabolite, carbamazepine-10,11-epoxide, in human plasma using high-performance liquid chromatography. Anal Bioanal Chem., 386(6), 1931-1936.
- Mandrioli, R., Albani, F., Casamenti, G., Sabbioni, C. & Raggia, M. A. (2001). Simultaneous high-performance liquid chromatography determination of carbamazepine and five of its metabolites in plasma of epileptic patients. J Chromatogr B Biomed Sci Appl., 762(2), 109-116.
- Bhatti, M. M., Hanson, G. D. & Schultz, L. (1998). Simultaneous determination of phenytoin, carbamazepine, and 10,11-carbamazepine epox-ide in human plasma by high-performance liquid chromatography with ultraviolet detection. J Pharm Biomed Anal., 16(7), 1233-1240.
- Ezzeldin, E., Shahat, A. A. & Basudan, O. A. (2013). Development and validation of an HPLC method for the determination of carbamazepine in human plasma. Life Science Journal., 10(4), 2159-2163.
- Dordevic, S., Kilibarda, V. & Stojanovic, T. (2009). Determination of carbamazepine in serum and saliva samples by highperformance liquid chromatography with ultraviolet detection. Vojnosani Pregl., 66(5), 347-352.
- Yoshida, T., Imai, K., Motohashi, S., Hamano, S. & Sato, M. (2006). Simultaneous determination of zonisamide, carbamazepine and carbamaz-epine-10,11-epoxide in infant serum by high-performance liquid chromatography. J Pharm Biomed Anal., 41(4), 1386-1390.
- Kishore, P., Rajnarayana, K., Reddy, M. S., Sagar, J. V. & Krishna, D. R. (2003). Validated high performance liquid chromatographic method for simultaneous determination of phenytoin, phenobarbital and carbamazepine in human serum. Arzneimittelforschung, 53(11), 763-768.
- Patil, K. M. & Bodhankar, S. L. (2005). Simultaneous determination of lamotrigine, phenobarbitone, carbamazepine and phenytoin in human serum by high-performance liquid chromatography. J Pharm Biomed Anal., 39(1-2), 181-186.
- Hallbach, J., Vogel, H. & Guder, W. G. (1997). Determination of lamotrigine, carbamazepine and carbamazepine epoxide in human serum by gas chromatography mass spectrometry. Eur J Clin Chem Clin Biochem., 35(10), 755-759.
- Minkova, G. & Getova, D. (2001). Determination of carbamazepine and its metabolite carbamazepine-10,11-epoxide in serum with gas-chromatography mass spectrometry. Methods Find Exp Clin Pharmacol., 23(9), 481-485.
- Steijns, L. S., Bouw, J. & van der Weide, J. (2002). Evaluation of fluorescencepolarization assays for measuring valproic acid, phenytoin, carbamazepine and phenobarbital in serum. Ther Drug Monit., 24(3), 432-435.
- Long, X. & Chen, F. (2013). Determination of carbamazepine in human urine and serum samples by high‐performance liquid chromatography with post-column Ru(bipy)32+- Ce(SO4)2 chemiluminescence detection. J Biological and Chemical Luminescence., 28(2), 211-216.
- Shimoyama, R., Ohkubo, T. & Sugawara, K. (2000). Monitoring of carbamazepine and carbamazepine 10,11-epoxide in breast milk and plasma by high-performance liquid chromatography. Ann Clin Biochem., 37(2), 210-215.
- Thejaswini, J. C., Gurupadayya, B. M. & Ranjith K. K. (2013). Quantitative determination of duloxetine HCL in human plasma by GC-FID method. Int J Pharm Pharmaceut Sci., 5, 405-408.
- Mercolini, L., Mandrioli, R., Cazzolla, R., Amore, M. & Raggi, M. A. (2007). HPLC analysis of the novel antidepressant duloxetine in human plasma after an original solid-phase extraction procedure. J Chromatogr B., 856(1-2), 81-87.
- Veeragoni, A.K., Sindgi V. M. & Satla, S. R. (2016). Validated LC-MS bioanalytical method for the estimation of duloxetine hydrochloride in human plasma. Scholars Research Library, Der Pharmacia Lettre., 8(8), 355-360.
- Reddy, D. C., Bapuji, A. T., Rao, V. S., Himabindu V., Raju, D. R., Syedba, S. & H. L. V. Ravikirani, H. L. V. (2012). Development and validation of a LC/MS/MS method for the determination of duloxetine in human plasma and its application to pharmacokinetic study. J Chem., 9(912568), 899-911.
- Bhanupriya, K Savithri Shivakumar, S., Ravi, A., Ramanjaneyulu, K. V., Venkateswara, P., Rao, A.M.S. & Babu, S. (2013). Bioanalytical method development and validation for estimation of duloxetine hydrochloride in human plasma using LC-MS/MS. Asian J Pharm Anal Med Chem., 1(1), 18-38.
- Johnson, J. T., Oldham, S. W. & Lantz R. J. (1996). Determination of duloxetine HCL in human serum using LC-MS/MS. J Liq Chromatogr Rel Technol., 19, 1631- 1635.
- Soni, P., Mariappan, T. T. & Banerjee, U. C. (2005). Determination of duloxetine HCL in human serum and biological fluids using high performance liquid chromatography. Talanta, 2005, 975-978.
- Mercolini, L., Mandrioli, R. & Cazzolla R. (2007). Determination of duloxetine HCL in human serum and biological fluids using high performance liquid chromatography. J Chromatogr. B., 856(1-2), 81-87.
- Bailey, D. N. & Jatlow, P. (1976). Gas chromatographic analysis for therapeutic concentrations of lmiprarnine and desipramine in plasma, with use of a nitrogen detector. Clin Chem., 22(10), 1697-1701.
- Moody, J. P., Tait, A. C. & Todrick, A. (1967). Plasma levels of imipramine and desmethylimipramine during therapy. Br. J. Psychiatry., 113(495), 183-187.
- Weder, H. J. & Bickel, M. H. (1968). Separation and determination of imipramine and its metabolites from biological samples by gas-liquid chromatography. J. Chromatogr., 37(2), 181-189.
- Onal, A. & Oztung, A. (2011). A rapid and simple RP-HPLC method for quantification of desipramine in human plasma. Review in Analytical Chemistry, 30(3-4).
- Belvedere, G., Burti, L., Frigerio,A. & Pantarotto,C. (1975). Gas chromatographic-mass fragmentographic determination of “steady-state” plasma levels of inipramine and desipramine in chronically treated patients. J Chromatogr., 111, 313-.317.
- Nagy, A. & Treiber, L. (1973). Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thin-layer chromatograms. J Pharm Pharmacol., 25(8), 599-604.
- Chinn, D. M., Jennison, T. A., Crouch, D. J., Peat, M. A. & Thatcher, G. W. (1980). Quantitative analysis for tricyclic antidepressant drugs in plasma or serum by gas chromatography chemical-ionization mass spectrometry. Cliin Chem., 26(8), 1201-I 204.
- Zhu, Z. & Neirinck, L. (2002). High-performance liquid chromatographic method for the determination of gabapentin in human plasma. J. Chromatogr B., 779(2), 307-312.
- Jalalizadeh, H., Souri, E., Tehrani, M. B. & Jahangiri, A. (2007). Validated HPLC method for the determination of gabapentin in human plasma using pre-column derivatization with 1-fluoro-2,4-dini-trobenzene and its application to a pharmacokinetic study. J Chromatogr B., 854(1-2), 43-47.
- Gauthier, D. & Gupta, R. (2002). Determination of gabapentin in plasma by liquid chromatography with fluorescence detection after solid-phase extraction with a C18 column. Clin Chem., 48(12), 2259-2261.
- Forrest, G., Sills, G. J., Leach, J. P. & Brodie, M. J. (1996). Determination of gabapentin in plasma by high-performance liquid chromatography. J Chromatogr B., 681(2), 421-425.
- Ifa, D. R., Falci, M., Moreas, M. E., Berreza, F. A. & Moraes M. O. (2001). Gabapentin quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study. J. Mass Spectrom., 36(2), 188-194.
- Ojha, A., Rathod, R., Patel, C. & Padh, H. (2007). LC-MS determination of gabapentin from human plasma. Chromatographia, 66(11-12), 853-857.
- Ramakrishna, N. V., Vishwottam, K. N., Koteshwara, M., Manoj, S., Santosh, M., Chidambara, J., Sumatha, B. & Varma, D. P. (2006). Rapid quantification of gabapentin in human plasma by liquid chromatography/tandem mass spectrometry. J Pharm Biomed Anal., 40(2), 360-368.
- Chang, S. Y., Wang, F. Y. (2004). Determination of gabapentin in human plasma by capillary electrophoresis with laser-induced fluorescence detection and acetonitrile stacking technique. J Chromatogr. B: Biomed Appl., 799(2), 265-270.
- Wolf, C. E., Saady, J. J. & Polkis A. (1996). Determination of gabapentin in serum using solid-phase extraction and gas-liquid chromatography. J Anal. Toxicol., 20(6), 498-501.
- Vermeij, T. A. & Edelbroek, P. M. (2004). Simultaneous high-performance liquid chromatographic analysis of pregabalin, gabapentin and vigabatrin in human serum by precolumn derivatization with o-phtaldialdehyde and fluorescence detection. J Chromatogr B., 810(2), 297-303.
- Tang, P. H., Miles, M. V., Glauser, T. A. & DeGrauw, T. (1999). Automated microanalysis of gabapentin in human serum by high-performance liquid chromatography with fluorometric detection. J Chromatogr B., 727(1-2), 125-129.
- Bahrami G. & Kiani, A. (2006). Sensitive high-performance liquid chromatographic quantitation of gabapentin in human serum using liquid-liquid extraction and pre-column derivatization with 9-fluo-renylmethyl chloroformate. J Chromatogr B., 835(1-2), 123-126.
- Qiboand, J. & Shuguang, L. (1999). Rapid high-performance liquid chromatographic determination of serum gabapentin. J Chromatogr B., 727, 119-123.
- Kushnir, M. M., Crossett, J., Brown, P. I. & Urry, F. M. (1999). Analysis of gabapentin in serum and plasma by solid-phase extraction and gas chromatography-mass spectrometry for thera6peutic drug monitoring. J Anal Toxicol., 23(1), 1-6.
- Borrey, D. C., Godderis, K. O., Engelrelst, V. I., Bernard, D. R. & Langlois, M. R. (2005). Quantitative determination of vigabatrin and gabapentin in human serum by gas chromatography-mass spectrometry. Clin Chim Acta., 354(1-2), 147-151.
- Gambelunghe, G., Tantucci, M. M. & Ambrosini, M. V. (2004). Gas chromatography-tandem mass spectrometry analysis of gabapentin in serum. Biomed Chromatogr., 19(1), 63-67.
- Hengy H. & Kolle, E. U. (1985). Determination of gabapentin in plasma and urine by high-performance liquid chromatography and pre-column labelling for ultraviolet detection. J Chromatogr., 341(2), 473-478.
- Wad, N. & Krämer, G. (1998). Sensitive high-performance liquid chromatographic method with fluorometric detection for the simultaneous determination of gabapentin and vigabatrin in serum and urine. J Chromatogr., 705(1), 154-158.
- Olcay Sagirli, Sevil Müge Cetin & Armağan Onal (2006). Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV-vis detection. Journal of Pharmaceutical and Biomedical Analysis, 42(5), 618-624.
- Khanvilkar, V., Shah, J. & Kadam, V. (2013). Development and validation of HPLC assay for estimation of irbesartan in human plasma. Research J Pharmacy and Technology, 6(3), 292-295.
- Bae, S. K., Kim, M., Shim, E. & Cho, D. (2009). HPLC determination of irbesartan in human plasma: its application to pharmacokinetic studies. Biomed Chromatogr., 23(6), 568-572.
- González, L., López, J. A. & Alonso, R. M. (2002). Fast screening method for the determination of angiotensin II receptor antagonists in human plasma by high-performance liquid chromatography with fluorimetric detection. J Chromatogr A., 949(1-2), 49-60.
- Katteyoma, M. Y., Pilli, N. R., Inamadugu, J. K. & Satyla, R. (2015). LC-MS/MS assay for irbesartan in human plasma using solid phase extraction technique: a pharmacokinetic study. Int J Pharm Pharma Sci., 7(9), 335-340.
- Tutunji, L. F., Tutunji, M. F., Mamoun, I. A., Khabbasand, M. H. & Adi I Arida, I. A. (2010). Simultaneous determination of irbesartan and hydrochlorothiazide in human plasma using HPLC coupled with tandem mass spectrometry: Application to bioequivalence studies. J Pharmacy Res., 51(4), 985-990.
- Qiua, X., Wangb, Z., Wanga, B., Zhana, H., Panc, X. & Xuc, R. (2014). Simultaneous determination of irbesartan and hydrochlorothiazide inhuman plasma by ultra high performance liquid chromatography tandem mass spectrometry and its application to a bioequivalence study. J Chromatogr B., 957, 110-115.
- Lee, H. W., Ji, H. Y., Park, E., Choon, K., Hye, L. & Lee, S. (2014). Hydrophilic interaction chromatography-tandem mass spectrometric analysis of irbesartan in human plasma: Application to pharmacokinetic study of irbesartan. J Separation Sci., 32(14), 112-117.
- Yousheng, A., Chuhong, X. & Huating, C. (2004). Determination of irbesartan in serum by HPLC, China Pharmacist 2004.
- Li, Z., Chen, F., Wang, X. & Wang, C. (2014). Ionic liquids dispersive liquid-liquid microextraction and high-performance liquid chromatographic determination of irbesartan and valsartan in human urine. Biomed Chromatogr., 27(2), 254-258.
- Ziegler, V. E., Taylor, J. R., Wetzel, R. D. & Biggs, J. T. (1978). Nortriptyline plasma levels and subjective side effects. British J Psychiatry., 132(1), 55-60.
- Braithwaite, R. A. & Widdop, B. (1971). A specific gas-chromatographic method for the measurement of 'steady-state' plasma levels of amitriptyline and nortriptyline in patients. Clinica Chimica Acta., 35(2), 461-472.
- Dahl, S. R., Olsen, K. M. & Strand, D. H. (2012). Determination of γ-hydroxybutyrate (GHB), β-hydroxybutyrate (BHB), pregabalin, 1,4-butane-diol (1,4BD) and γ-butyrolactone (GBL) in whole blood and urine samples by UPLC-MSMS. J Chromatogr B Analyt Technol Biomed Life Sci., 885-886, 37-42.
- Thejaswini, J. C., Gurupadayya, B. M. & Raja, P. (2012). Gas chromatographic determination of pregabalin in human plasma using ethyl chloroformate derivatizing reagent. J Pharmacy Research., 5(6), 3112-3116.
- Berry, D. & Millington, C. (2005). Analysis of pregabalin at therapeutic concentrations in human plasma/serum by reversed-phase HPLC. Ther Drug Monit., 27(4), 451-456.
- Mandal, U., Sarkar, A. K., Gowda, K. V., Agarwal, S., Bose, A., Bhaumik, U., Ghosh, D. & Pal, T. K. (2008). Determination of pregabalin in human plasma using LC-MS-MS. Chromatographia., 67(3-4), 237-243.
- Nirogi, R., Kandikere, V., Mudigonda, K., Komarneni, P. & Aleti, R. (2009). Liquid chromatography atmospheric pressure chemical ionization tandem mass spectrometry method for the quantification of pregabalin in human plasma. J Chromatogr B., 877(30), 3899 -3906.
- Shah, G. R., Ghosh, C. & Thaker, B. T. (2010). Determination of pregabalin in human plasma by electrospray ionisation tandem mass spectroscopy. J Adv Pharm Tech Res., 1(3), 354-357.
- Vaidya, V. V., Yetal, S. M., Roy, S. M. N., Gomes, N. A. & Joshi, S. S. (2007). LC-MS-MS Determination of pregabalin in human plasma. Chromatographia, 66(11-12), 925-928.
- Arayne, M. S., Shahnaz, H., Ali, A. & Sultana, N. (2014). Monitoring of pregabalin in pharmaceutical formulations and human serum using UV and RP-HPLC Techniques: Application to dissolution test method. Pharm Anal Acta., 5(2), 287 291.
- Gujral, R. S., Haque, S. K. & Sanjeev Kumar, K. S. (2009). A novel method for the determination of pregabalin in bulk pharmaceutical formulations and human urine samples. Afr J Pharm Pharmacol., 3(6), 327-334.
- Kokubun, H., Honma, M., Miyano, K. & Uezono, Y. (2018). A novel method for determination of tapentadol in the serum of cancer patients by high-performance liquid chromatography with electrochemical detection. Jpn J Pharm Palliat Care Sci., 11, 131-133.
- Hillewaert, V., Pusecker, K., Sips, L., et al. (2015). Determination of tapentadol and tapentadol-O-glucuronide in human serum samples by UPLC-MS/MS. J Chromatogr B Anal Technol Biomed Life Sci., 981-982, 40-47.
- Coulter, C., Taruc, M., Tuyay, J. & Moore, C. (2010). Determination of tapentadol and its metabolite n-desmethyltapentadol in urine and oral fluid using liquid chromatography with tandem mass spectral detection. J Anal Toxicol., 34(8), 458-463.
- Bourland, J. A., Collins, A. A., Chester, S. A., Ramachandran, S. & Backer, R. C. (2010). Determination of tapentadol (nucynta) and N-desmethyltapentadol in authentic urine specimens by ultra-performance liquid chromatography-tandem mass spectrometry. J. Anal. Toxicol., 34(8), 450-457.
- Haage, P., Kronstrand, R., Carlsson, B., Kugelberg, F. C. & Josefsson, M. (2016). Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS. J Pharm BioMed Anal., 119, 1-9.
- Baconi, D., Stan, M., Ebrahim, Z. A., Tuchila, C. & Balalau, C. (2016). Determination of tramadol in human plasma by HPLC with fluorescence detection. J Mind Med Sci., 3(1), 55-64.
- Curticapean, A., Muntean, D., Curticapean, M., Dogaru, M. & Vari, C. (2008). Optimized HPLC method for tramadol and O-desmethyl tramadol determination in human plasma. J Biochem Biophys Methods., 70(6), 1304-1312.
- Ebrahimzadeh, H., Yamini, Y., Sedighi, A. & Rouini, M. R. (2008). Determination of tramadol in human plasma and urine samples using liquid phase microextraction with back extraction combined with high performance liquid chromatography. J Chromatogr B Anal Technol Biomed Life Sci., 863(2), 229-234.
- Gu, Y. & Fawcett, J. P. (2005). Improved HPLC method for the simultaneous determination of tramadol and O-desmethyltramadol in human plasma. J Chromatogr B., 821(2), 240-243.
- Nobilis, M., Kopecky, J., Kvetina, J. & Svoboda, Z. (2002). High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma. Application to a bioequivalence study in humans. J Chromatogr A., 949(1-2), 11-22.
- Ceccato, A., Vanderbist, F., Pabst, J. Y. & Streel, B. (2000). Enantiomeric determination of tramadol and its main metabolite O-desmethyltramadol in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl., 748(1), 65-76.
- Patel, B. N., Sharma, N., Sanyal, M. & Shrivastav, P. S. (2009). An accurate, rapid and sensitive determination of tramadol and its active metabolite O-desmethyltramadol in human plasma by LC-MS/MS. J Pharm BioMed Anal., 49(2), 354-366.
- Papoutsis, I., Khraiwesh, A., Nikolaou, P., Pistos, C., Spiliopoulou, C. & Athanaselis, S. (2012). A fully validated method for the simultaneous determination of 11 antidepressant drugs in whole blood by gas chromatography-mass spec-trometry. J Pharm Biomed Anal., 70, 557-562.
- Vu, R. L., Helmeste, D., Albers, L. & Reist, C. (1997). Rapid determination of venlafaxine and O-desmethylvenlafaxine in human plasma by high-performance liquid chromatography with fluorimetric detection. J Chromatogr B Biomed Sci Appl., 703(1-2), 195-201.
- Raut, B. B., Kolte, B. L., Deo, A. A., et al. (2003). A rapid and sensitive HPLC method for the determination of venlafaxine and O‐desmethylvenlafaxine in human plasma with UV detection. J Liq Chromatogr. Related. Technol., 26(8), 1297-1313.
- Clement, E. M., Odontiadis, J. & Franklin, M. (1998). Simultaneous measurement of venlafaxine and its major metabolite, oxydesmethylvenlafaxine, in human plasma by high-performance liquid chromatography with coulometric detection and utilisation of solid-phase extraction. J Chromatogr B Biomed Sci Appl., 705(2), 303-308.
- Kang, H., Kang, M., Kim, H., Park, Y., Kim, S. & Kang, J. (2014). Development of a LC-MS/MS for quantification of venlafaxine in human plasma and application to bioequivalence study in healthy Korean subjects. Translational and Clinical Pharmacology, 22(1), 35-42.
- Bhatt, J., Jangid, A., Venkatesh, G., Subbaiah, G. & Singh, S. (2005). Liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for simultaneous determination of venlafaxine and its active metabolite O-desmethyl venlafaxine in human plasma. J Chromatogr B Anal Technol Biomed Life Sci., 829(1-2), 75-81.
- Wei, Z., Bing-Ren X. & Cai-Yun, W. (2007). Liquid chromatography-mass spectrometry method for the determination of venlafaxine in human plasma and application to a pharmacokinetic study. Biomed Chromatogr., 21(3), 266-272.
- Patel, B. N., Sharma, N., Sanyal, M. & Shrivastav, P. S. (2008). Liquid chromatography tandem mass spectrometry assay for the simultaneous determination of venlafaxine and O-desmethylvenlafaxine in human plasma and its appli-cation to a bioequivalence study. J Pharm Biomed Anal., 47(3), 603-611.
- Qin, F., Li, N., Qin, T., et al. (2010). Simultaneous quantification of venlafaxine and O-desmethylvenlafaxine in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study. J Chromatogr B Anal Technol Biomed Life Sci., 878(7-8), 689-694.
- Rudaz, S., Stella, C., Balant-Gorgia, A. E., Fanali, S. & Veuthey, J. L. (2000). Simultaneous stereoselective analysis of venlafaxine and O-desmethylvenlafaxine enantiomers in clinical samples by capillary electrophoresis using charged cyclodextrins. J Pharm Biomed Anal., 23(1), 107-115.
- Waschqler, R., Moll, W., Koniq, P., et al. (2004). Quantification of venlafaxine and O-desmethylvenlafaxine in human serum using HPLC analysis. Int J Clin Pharmacol Ther., 42(12), 724-728.