Intra Nasal Drug Delivery to Reduce Chronic Pain: A Critical Review

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Abstract:

Chronic pain is a severe disorder which includes fibromyalgia, rheumatoid arthritis, cancer-related pains, etc. Pains are very severe in the age above 60 like arthritis pains. The prevalence of chronic pain is high in developed and developing countries. There is a significant increase in chronic pain prevalence studies in the world. Chronic pain is a severe condition were treatments are offered with NSAIDs, topical formulations, sprays, etc. these medications can offer only a temporary relief. There is no permanent relief for chronic pains. Pain is an immune-mediated disorder which leads to sleeplessness, stress, tired, etc. Normally chronic pains cannot be cured by treatment with modern medicines, but they are available with severe toxic effects. Treatment is available with pain relievers which may give a temporary relief but with severe side effects. Treatments with herbal remedies are available with essential oils as a combination of different essential oils which can be used as an oil bath these oils can relieve pain to some extent and can give a relief to patients with chronic pain. Hence when a plant containing essential oil is selected the plant must contain active constituents which include secondary metabolites etc. The selected plant must be free from side effects and toxicity, should be having better potency and efficacy, and safe to use. Nasal sprays are agents which can deliver medicaments directly to the brain by targeting pain receptors in the brain. Nasal sprays are more efficient way of administering drugs with potential use in crossing the blood-brain barrier. This review mainly focuses on intra-nasal drug delivery and transport of drugs through the olfactory route and also reviews the recent development in nanotechnology and role of Nanoparticles used in the nose-to-brain drug delivery.

Introduction

Chronic pains like fibromyalgia, rheumatoid arthritis, neuropathic pain, etc are most common pain disorders, affecting 5% of the world population. According to the American College of Rheumatology, chronic pain affects between 2 and 4 percent of people. Up to 90 percent of people with the condition are women. Essential oil has been reported to reduce the severity of pain, anxiety, and depression, and improve the quality of sleep, suggesting that it may be useful to treat chronic pain. Chronic pain, a disease of pain perception, is a long-term chronic illness affecting 0.5-2% of general population. Females are 3-7 times more frequently affected than males and 10-16% patients can have an associated rheumatologic condition. The prevalence of the disease is high in developed and developing countries. There is a significant increase in chronic pain prevalence studies in the world. Chronic pain is a severe condition were treatments are offered with NSAIDs, topical formulations, sprays, etc. these medications can offer only a temporary relief. Chronic pains may be muscular disorders which include fibromyalgia, rheumatoid arthritis, and neuropathic pain, symptoms of chronic pain include joint pain, muscle aches, burning pain, fatigue, sleep problems, loss of stamina and flexibility, due to decreased activity, mood problems, including depression, anxiety, and irritability. Causes of chronic pain include osteoarthritis, rheumatoid arthritis, back pain, fibromyalgia, inflammatory bowel disease, surgical trauma, advanced cancer. Chronic pain causes are due to pain disorders like chronic fatigue syndrome, endometriosis, fibromyalgia, inflammatory bowel disease, interstitial cystitis, temporomandibular joint dysfunction. Some of the most common types of chronic pain include headache, postsurgical pain, post-trauma pain, lower back pain, cancer pain, arthritis pain, neurogenic pain, psychogenic pain. This review mainly focuses on the various pathways involved in intra nasal drug delivery and transport of drugs through the olfactory route and trigeminal pathway and also reviews the recent development in nanotechnologies and Nanoparticles used in the nose-to-brain drug delivery.

Nasal sprays are agents which can deliver medicaments directly to the brain by targeting pain receptors in the brain. Nasal sprays are used to deliver medications locally through the nasal cavities systemically. The nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to pills or injection. Substances can be administered directly and quickly through the nose.[1] Many formulations exist as nasal sprays for systemic administration e.g. treatments for pain, migraine, osteoporosis, rhinitis, and sinusitis. Nasal sprays are more efficient way of administering drugs with potential use in crossing the blood-brain barrier. The delivery of the drug via an intra nasal route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. A new method of fast-acting pain control, in which patients can administer themselves powerful doses of a pain reliever with a nasal spray, which shows promising effect for people with chronic pain. Nasal sprays are patient-friendly and administration of drug through this route is easy and convenient for the patients. Researchers are testing this method for delivery of short-acting but strong pain relievers hence pain relievers are rapidly absorbed through the nasal route.

Figure 2 Drug deliveries through Nasal route

Intranasal drug delivery system has emerged as an alternative route over the systemic oral and parenteral drug delivery administration through nose to brain drug delivery. Nasal sprays are more efficient way of administering drugs with potential use in crossing the blood-brain barrier. The delivery of the drug via an intra nasal route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb enhances the drug bioavailability in the brain and reduces the side effects, drug degradation, and wastage of the drug through systemic clearance. However, there are also some drawbacks associated with INDD like poor drug permeation through the nasal mucosa and mucociliary clearance. Some factors may affect the rate of drug absorption these factors are formulation of the drug, drug permeation and metabolic stability. Many CNS-associated diseases have already been treated with IN administration of drugs, like Alzheimer’s disease, Parkinson’s disease, Huntington’s Disease, depression, anxiety, autism, meningitis, seizure, addiction, schizophrenia, stroke, etc. Intranasal administration is an alternative option to enteral or intravenous administration. Numerous new promising drugs are under development for IN application for diseases like Parkinson’s disease, depression, anxiety, autism, seizure, addiction, and stroke. Many intranasal medications are still in preclinical phase of development. Some of these studies are targeting memory and learning that show potential treatment for neurodegenerative disorders like AD, PD, epilepsy, and other neurotoxic events like oxidative stress and ischemia, and other diseases.

Figure 3 Route of administration

Essential oil also aids in treating migraine pains, gout pains, rheumatism, and headaches due to cold. Essential oil is also widely used in the healing of muscular spasms. Essential oils have been used for thousands of years for its calming, relaxing, balancing influences, and stabilizing effects. Essential Oil used in Ayurveda and aromatherapy commonly offers a calming and restorative effect due to the high amounts of terpenoids in the oil. Due to these properties, essential oil can be used as an alternative treatment to assist restlessness, sleeplessness, and trauma. During the last three decades, it has been clinically investigated for its relaxing properties. Researchers have pinpointed that terpenes act as active constituents that exert a calming and restorative effect on the central nervous system. Essential oils are used as stress releasing, calming and relaxing, antispasmodic, analgesic, anti-inflammatory, tranquilizer, and temperature-reducing. Essential oil can be effective in treating sleeping disorders such as insomnia and may also be used to relive symptoms caused by PMS such as headaches, diarrhea, stomach cramps, fatigue, migraines, and indigestion. Essential oil is calming and relaxing on the nervous system and can be beneficial for depression, restlessness, anxiety, stress, and emotional trauma. Still it is required to design the formulation having combined advantages such as Nanostructured lipid carriers for intranasal delivery,[25] and in situ nasal gel,[27] chitosan coated nanostructured lipid carrier, etc. Researchers are still searching for new technologies for improve the bio efficacy via IN administration route.

Role of Nanoparticles in Intranasal drug delivery

Nanoparticles play a crucial role in delivering the drug to the targeted site of action through many routes like oral, systemic, parenteral, and other routes. Nanoparticles including, carbon-based nanoparticles, biodegradable nanoparticles, metallic nanoparticles, polyester-based nanoparticles, nanostructured lipid carriers lipid-based nanoparticles, liposomes, nanoemulsions, micelles, and nano complexes exhibit significant advantages in enhancement of brain delivery of intranasally administrated drugs. Nanoparticles with antibodies on the surface have the capability to cross the brain barrier and also provide neuroprotection.

Conclusion

Nasal drug delivery systems is a new technology for pain management, since solid dosage forms like tablets, capsules, gels were commonly used for pain management, transdermal drug delivery systems like transdermal patches was one of the best treatment for managing pain. Transdermal patches are available via the skin into cutaneous and subcutaneous tissues through the semi-permeable membranes into the systemic circulation enhanced permeability increases the efficacy of the drug through these passages. Nanoparticles play a crucial role in delivering the drug to the targeted site of action through many routes like oral, systemic, parenteral, and other routes. Researchers are still working on testing this method for delivery of short-acting but strong pain relievers since pain relievers are rapidly absorbed through the nasal route. Relieving pain through nasal route is an alternative therapy to reduce the side effects increase the potency efficacy and safety using herbal remedies and improve the technology by using new methods to overcome the difficulties in formulating finished products.

References

Mills SEE1, Nicolson KP2, Smith BH Chronic pain: a review of its epidemiology and associated factors in population-based studies. Br J Anaesth. 2019 Aug;123(2):e273-e283..
María Dueñas,1 Begoña Ojeda,2 Alejandro Salazar,2 Juan Antonio Mico,3 and Inmaculada Failde2A review of chronic pain impact on patients, their social environment and the health care systemJ Pain Res. 2016; 9: 457–467.
Krishnan V. Chakravarthy, MD, PhD,*,† Frank J. Boehm,‡ and Paul J. Christo, MD, MBA
Nanotechnology: A Promising New Paradigm for the Control of Pain Pain Medicine 2018; 19: 232–243
Siavash Beiranvand &Mohamad Masud Sorori Pain management using nanotechnology approaches Artificial Cells, Nanomedicine, and Biotechnology Volume 47, 2019 – Issue 1 Pages 462-468

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Intra Nasal Drug Delivery to Reduce Chronic Pain: A Critical Review

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