Formulation and Evaluation of Herbal-Based Prophylactic Migraine Pain Relief Balm

Overview of Migraines

Migraine is a primary headache disorder characterized by recurrent, moderate to severe headaches that are often unilateral and pulsating, lasting between 4 to 72 hours (1). It is frequently associated with nausea, vomiting, photophobia (sensitivity to light), and phonophobia (sensitivity to sound), all of which significantly impair quality of life (2). The International Classification of Headache Disorders (ICHD-3) categorizes migraines into two types:

1. Migraine with aura – This type includes transient neurological disturbances, such as visual changes (flashes of light, blind spots) or sensory changes (tingling, numbness), before the headache begins (3).
2. Migraine without aura – The more common form of migraine, occurring without these warning signs (3).

Headache disorders—including migraines, tension-type headaches (TTH), and cluster headaches— affect nearly 40% of the global population (3.1 billion people in 2021) (4). Migraine alone impacts approximately 1.1 billion people worldwide (5). It is three times more common in women than men, largely due to hormonal influences (6). Migraines usually start at puberty and are most common in people aged 35–45 years, though they also affect children and adolescents (4).  The impact of migraines extends far beyond pain. It is one of the leading causes of disability adjusted life years (DALYs) worldwide, affecting daily life, work productivity, education, and mental health (4). Many migraine sufferers also experience anxiety and depression, further worsening their quality of life (7). Despite its significant burden, a large number of people remain undiagnosed or untreated, increasing both personal and economic challenges (4).

Existing Treatments for Migraines

Migraine occurs due to dysfunction of the trigeminovascular system, involving cortical spreading depression, neurogenic inflammation, and pain sensitization mediated by calcitonin gene-related peptide (CGRP) (8). Current treatment approaches aim to relieve acute symptoms and prevent future attacks, categorized as follows:

• Acute therapies – Used for immediate relief during an attack, including nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergotamines, and CGRP antagonists (9).
• Preventive therapies – Reduce migraine frequency and severity. Common options include beta-blockers, anti-epileptic drugs (topiramate, valproic acid), antidepressants (amitriptyline), and CGRP monoclonal antibodies (9, 10).

The Role of Topical Treatments

Due to the limitations of oral migraine medications, topical treatments have gained attention as effective alternatives for migraine relief (4). Unlike oral drugs, topical formulations work locally, allowing direct absorption through the skin while minimizing systemic side effects (11). Advantages of Topical Treatments

• Localized effect – Targets the affected area directly instead of impacting the entire body (11).
• Fewer systemic side effects – Reduces gastrointestinal and cardiovascular risks commonly associated with oral drugs (11). 
• Improved patient compliance – Non-invasive, easy to use, and provides immediate cooling and analgesic effects (11). 

METHODOLOGY

• Materials used

1. Lavender Oil (Lavandula angustifolia)

Fig.  Lavender Oil (Lavandula angustifolia)

• • Source & Extraction

• • Lavender essential oil is extracted from the flowers of Lavandula angustifolia through steam distillation, preserving its bioactive compounds.
  • The main constituents are linalool (28.19%) and linalyl acetate (34.90%), which contributes to its analgesic, anti-inflammatory, and calming effects.

• • Therapeutic Role in Migraine Relief by Topical Application:

• •  Anti-inflammatory Action: Linalyl acetate inhibits NF-κB activation, reducing neurogenic inflammation involved in migraines.
  • Vasodilatory Effect: Lavender oil relaxes blood vessels, improving circulation and relieving migraine-related tension.
  • Pain Modulation: Linalool interacts with opioid and cannabinoid receptors, contributing to neuropathic pain relief.
  • GABAergic Activity: Enhances GABA-A receptor function, exerting a calming effect on the nervous system that helps alleviate migraine symptoms.

• • Aromatherapy Benefits:

• • Inhalation of lavender oil vapours stimulates the olfactory system, leading to the activation of limbic structures (which regulate emotions and pain perception).
  • Clinical studies show that lavender oil inhalation can reduce migraine severity and frequency when combined with topical application.
  • The combined effect of topical absorption and inhalation enhances its therapeutic potential for migraine relief.

• • Skin Penetration & Absorption

• • Lipophilic nature allows lavender oil to penetrate the stratum corneum, accumulating in the epidermis and dermis for 4–6 hours.
  • Functions as a natural penetration enhancer, improving transdermal absorption of other active ingredients in the balm.
  • Encapsulation in lipid-based carriers improves retention and prevents rapid evaporation, increasing efficacy.

• • Compatibility with Balm Base Ingredients

• • Highly compatible with lipid-based excipients such as beeswax, shea butter, and carrier oils.
  • Shows no adverse interactions with methyl salicylate or camphor, making it suitable for multi-ingredient formulations.
  • Volatility Considerations: Beeswax reduces evaporation losses, helping retain the active compounds.

• • Solubility & Stability in Semi-Solid Formulations

• • Solubility: Highly soluble in lipid-based formulations, but poorly soluble in water.
  • Stability Considerations: o Exposure to heat, light, and oxygen leads to degradation of linalool and linalyl acetate.
  • Stored in amber-coloured, airtight containers to maintain potency,
  • Recommended Addition Temperature: Should be added below 40°C to prevent thermal degradation.
  • Antioxidants (e.g., vitamin E) can be incorporated to prevent oxidative degradation.

• • Safety & Regulatory Considerations

1. • Recognized as Generally Recognized as Safe (GRAS) by the FDA.
   • Patch testing is advised before full application to rule out allergic reactions.
   • Mild skin irritation may occur in some individuals, particularly at higher concentrations.
2. Eucalyptus Oil (Eucalyptus globulus)            

Fig. Eucalyptus Oil (Eucalyptus globulus)

• • Source & Extraction

• • Eucalyptus oil is extracted from Eucalyptus globulus leaves through steam distillation, preserving its active compounds.
  • The primary constituents include 1,8-cineole (eucalyptol), α-pinene, and limonene, which contribute to its analgesic, anti-inflammatory, and muscle relaxant properties.

• • Therapeutic Role in Migraine Relief by Topical Application:

• • Anti-inflammatory Action: Eucalyptol inhibits pro-inflammatory cytokines (IL-6, TNF α, IL-1β), reducing neurogenic inflammation associated with migraines.
  • Analgesic Effect: Eucalyptus oil acts on nociceptive pain pathways, blocking pain transmission via TRPA1 and TRPM8 receptors, which also contribute to a cooling effect [24].
  • Muscle Relaxant Effect: The menthol-like cooling sensation provided by 1,8-cineole helps relieve migraine-related muscle tension [24].

• • Aromatherapy Benefits:
•  Eucalyptus oil is widely used in migraine aromatherapy, often in combination with       Lavender and Peppermint Oils [12].
• Inhalation activates olfactory receptors, triggering relaxation responses and reducing migraine intensity.
• Clinical surveys indicate that migraine sufferers commonly use Eucalyptus Oil via inhalation or topical application, reporting relief from its anti-inflammatory and cooling effects.
• Studies suggest that combined inhalation and topical application further enhance its efficacy in headache relief [19].
  • Skin Penetration & Absorption

• • The lipophilic nature of eucalyptol enables rapid penetration through the stratum corneum, reaching the dermal layers within minutes.
  • Functions as a natural permeation enhancer, improving the transdermal absorption of other active ingredients in the balm [24].
  • Encapsulation in lipid-based carriers (e.g., solid lipid nanoparticles) enhances retention, controlled release, and stability [24].

• Compatibility with Balm Base Ingredients

• Petroleum Jelly & Beeswax – Acts as a stable base for eucalyptus oil, ensuring sustained release and skin adherence [24].
  • Menthol & Camphor – Synergistic effects in pain relief and decongestion, enhancing therapeutic efficacy [24], [26].
  • Methyl Salicylate – Compatible and enhances anti-inflammatory effects, commonly combined in topical analgesics [24], [25].
  • Sodium Benzoate – No direct interaction noted, but generally used as a preservative in oil-based formulations [24].

• • Solubility & Stability in Semi-Solid Formulations

• • Solubility: Highly soluble in lipophilic formulations, poorly soluble in aqueous systems.
  • Stability Considerations:
  • Heat, light, and oxygen exposure lead to oxidation and degradation of eucalyptol [25]. o Stored in amber-coloured, airtight containers to maintain potency [25].
  • Recommended Addition Temperature: Should be added below 40°C to prevent thermal degradation [26].
  • Addition of antioxidants (e.g., vitamin E) helps prevent oxidative degradation [26].

• • Safety & Regulatory Considerations

• • Recognized as Generally Recognized as Safe (GRAS) by the FDA [17].
  • Patch testing is advised before full application to rule out allergic reactions [17].
  • May cause mild skin irritation in sensitive individuals, especially at higher concentrations.

3. Coconut Oil 

Fig. Coconut Oil

3.1 Source: Coconut oil is expressed from the dried solid part of endosperm of coconut, Coocos nucifera L.,     belonging to family palmae.

• 2. Uses in balm:
• Used as solvent to dissolve essential oils.
• Several studies have shown that virgin coconut oil has anti-inflammatory properties, due to                          high lauric acid levels. 

4. Beeswax (Emulsifier and Thickener)                                                   

Fig. Beeswax (Emulsifier and Thickener)

4.1 Source: Produced by honeybees (Apis mellifera).

4.2 Function:

• • Thickens the balm, giving it the desired consistency.
  • Acts as an emulsifying agent, ensuring uniform blending of ingredients.
  • Forms a protective barrier on the skin while allowing it to breathe.

4.3 Pharmacological Effects:

• • Moisturizing: Prevents skin dryness.
  • Anti-inflammatory: Helps reduce redness and irritation.
  • Antibacterial: Provides mild protection against infections.

4.4 Uses in Balm:

4. • Improves texture, stability, and spreadability.
   • Helps retain moisture and active ingredients on the skin.
5. Petroleum Jelly (Base & Skin Protectant)         

Fig. Petroleum Jelly (Base & Skin Protectant)

5.1 Composition: Semisolid mixture of hydrocarbons.

5.2 Function:

• • Acts as an occlusive agent, forming a protective barrier over the skin.
  • Prevents moisture loss, keeping the skin hydrated.
  • Enhances drug delivery by ensuring uniform dispersion of active ingredients.
  • Aids in wound healing and protects against external irritants.

5.3 Use in Balm:

• Improves spreadability and consistency of the formulation.
• Prevents dryness and cracking of the skin.

6. Menthol (Cooling agent and Counter-irritant)   

Fig. Menthol (Cooling agent and Counter-irritant)

6.1 Source: Derived from peppermint plant (Mentha arvensis).

6.2 Mechanism of Action:

• Activates TRPM8 (Transient Receptor Potential Melastatin-8) receptors, producing a cooling sensation.
• Desensitizes nociceptors, reducing pain perception.

6.3 Pharmacological Effects:

• Analgesic: Provides pain relief by altering nerve signalling
• Anti-inflammatory: Helps reduce swelling and irritation.
• Counter-irritant: Works by causing a mild irritation that distracts from deeper pain.

6.4 Use in Balm:

o Helps relieve headaches, muscle pain, and neuralgia.

o Provides a cooling effect, improving patient comfort.

7. Camphor (Counter-Irritant & Blood Flow Enhancer)

Fig. Camphor (Counter-Irritant & Blood Flow Enhancer)

7.1 Source: Extracted from Cinnamomum camphora.

MECHANISM OF ACTION:

o Stimulates blood circulation, producing a warming effect.

o Acts on sensory nerves, creating a mild irritation that reduces deeper pain perception.

7.3 Pharmacological Effects:

o Rubefacient (increases blood flow to applied area).

o Analgesic: Blocks pain signals at nerve endings.

o Antimicrobial & Antiseptic: Helps prevent skin infections.

7.4 Use in Balm:

o Enhances local circulation, aiding in pain relief.

o Commonly used for muscle and joint pain relief.

8. Sodium Benzoate (Preservative)                                   

Fig. Sodium Benzoate (Preservative)

8.1 Function:

o Prevents microbial growth (bacteria, fungi, yeast), extending product shelf-life.

o Ensures stability and safety of the formulation.

8.2 Use in Balm:

o Protects the balm from contamination and degradation.

o Maintains product consistency and effectiveness over time.

8.3 Regulatory Status: GRAS (Generally Recognized as Safe) when used within recommended limits.

• List of Ingredients used in the formulation.

• Method of preparation of herbal balm formulation

Step 1: Melting the Base Ingredients

1. Take a clean, dry beaker and place it on a hot plate or in a water bath at 50-60°C.
2. Add beeswax (1.5-2g) and petroleum jelly (2g) into the beaker and allow them to melt completely while stirring gently.
3. Once melted, add coconut oil (1.5ml) and mix well to ensure uniformity.

Step 2: Incorporating Menthol and Camphor

4. Reduce the temperature to below 50°C to prevent the evaporation of volatile components.
5. Add menthol (1g) and camphor (0.8g) to the melted base and stir until they dissolve completely.

Step 3: Adding Essential Oils (API)

6. Once the mixture is at 40°C or lower, add eucalyptus oil (0.6ml) and lavender oil (0.3ml).
7. Stir continuously to ensure uniform dispersion.

Step 4: Adding Preservative

8. Add vitamin E (0.2ml) or sodium benzoate (0.09g) and mix well.

Step 5: Pouring & Solidification

9. Pour the mixture into sterilized balm containers while still warm.
10. Allow it to cool at room temperature until it solidifies completely.

• Formulation Table

EVALUATION

A. Physical properties

The physical appearance of the formulation was checked visually.(25)

1. Colour

The formulation's colour was evaluated against a white background.

2. Consistency

The consistency was checked by applying the formulation to the skin.

3. Odour

The odour of the balm was evaluated by dissolving the balm in water and taking the smell.

4. Greasiness

The greasiness was measured through application on the skin.

5. Smoothness
   The smoothness of the formulation was examined by rubbing the balm between the fingers, noting whether it felt smooth, homogeneous, or rough.

B. Measurement of pH

The pH of the formulated product was measured by using digital pH meter by dipping the glass electrode in to the gel system to cover it completely. The measurement was performed in triplicate and the average of the three readings was recorded.(35)

C. Viscosity

The viscosity of balm was determined by using a Brookfield viscometer.

D. Stability

The physical stability of formulated balm was carried out for one month at room temperature.

E. Spreadability

Spreadability is expressed in terms of time taken by two slides to slip of from balm that is placed in between the slides under the direction of certain load. A shorter separation time indicates superior spreadability. Spreadability is performed by using the following formula:

S = M × L / T

Where,

S =Spreadability

M = weight tied to upper slide,

L =length of glass slides,

T = time take to separate the slides.

F. Washabiity

The balm was applied to the skin then washability with water was checked.(25)

G. Non-irritancy test

The formulated product was applied to the human skin and effects are observed.

RESULT AND DISCUSSION

The physicochemical characteristics of the formulated balm were assessed, including Colour, Odour, Consistency, Smoothness, Greasiness and pH. The formulation demonstrated an appealing appearance and quality with pH level ranging from 6.0 to 8.0, which is within the optimal range for balms. In this study, a migraine pain relief balm was formulated by using various excipients. The balm subsequently was evaluated for the following physical parameters and was found to be satisfactory in terms of appearance and texture. It was easily applicable with fingers, providing a smooth feel without any roughness. The smell of balm was found to be characteristic.