Pregabalin Phonophoresis and MET for Knee Osteoarthritis

Knee osteoarthritis is the most prevalent degenerative joint disease globally, characterized by progressive loss of articular cartilage, subchondral bone remodeling, synovial inflammation, and capsular thickening. While traditionally considered a nociceptive pain condition, accumulating evidence demonstrates that a significant subset of patients - particularly those with advanced radiographic severity - exhibit neuropathic pain features. This neuropathic component arises from peripheral nerve sensitization, central sensitization, and structural changes in both peripheral and central nervous systems.

Grade III knee osteoarthritis (Kellgren-Lawrence classification) represents severe cartilage loss with joint space narrowing, osteophyte formation, and subchondral sclerosis. In this population, neuropathic pain prevalence is substantially elevated compared to earlier grades. Clinical descriptors include burning sensations, electric shock-like pains, tingling, and allodynia.

Pregabalin, a gabapentinoid anticonvulsant, exerts its analgesic effect by binding to the alpha-2-delta subunit of voltage-gated calcium channels, reducing calcium influx and subsequent release of excitatory neurotransmitters including glutamate, norepinephrine, and substance P. While effective for neuropathic pain, oral administration produces dose-dependent central nervous system side effects that frequently limit tolerability and compliance.

Phonophoresis represents a transdermal drug delivery method utilizing therapeutic ultrasound to enhance skin permeability and drive medication into underlying tissues. The proposed mechanism involves cavitation, acoustic streaming, thermal effects, and alterations in stratum corneum lipid bilayer structure. Previous studies have demonstrated successful phonophoretic delivery of gabapentin (a pregabalin analog) for post-mastectomy neuralgia, with superior analgesia compared to topical gel alone.

Concurrently, lower extremity muscle dysfunction is well-documented in knee osteoarthritis. The gastrocnemius muscle, spanning both knee and ankle joints, exhibits increased stiffness measured by shear wave elastography. This stiffness alters plantar pressure distribution, increases knee joint compressive forces during gait, and contributes to reduced walking speed, stair-climbing difficulty, and overall mobility limitation.

Muscle energy technique is a manual therapy method classified under osteopathic and physiotherapeutic approaches. Post-isometric relaxation, a specific MET variant, involves voluntary isometric contraction of the target muscle against a precisely applied counterforce, followed by passive stretching during the subsequent relaxation phase. This technique is theorized to reset muscle spindle sensitivity, reduce Golgi tendon organ inhibition, and lengthen fibrotic or shortened muscle fibers.

Study Objectives

Primary Objective: To evaluate the effect of pregabalin-encapsulated hydrogel phonophoresis combined with gastrocnemius MET on neuropathic pain (measured by DN-4) in patients with Grade III knee osteoarthritis, compared to aqua gel phonophoresis with MET.

Secondary Objectives:

To compare the effect of the experimental intervention versus control on pain intensity (NPRS).

To compare the effect on functional mobility and stiffness (WOMAC total and subscale scores).

To document any adverse events associated with pregabalin phonophoresis.

Hypotheses

Null Hypothesis (H₀): There is no significant difference between pregabalin-encapsulated hydrogel phonophoresis plus MET versus aqua gel phonophoresis plus MET in reducing neuropathic pain, pain intensity, or improving mobility in Grade III knee osteoarthritis.

Alternative Hypothesis (H₁): Pregabalin-encapsulated hydrogel phonophoresis plus MET produces significantly greater improvement in neuropathic pain, pain intensity, and mobility compared to aqua gel phonophoresis plus MET.

Detailed Methodology

Screening and Recruitment

Potential participants will be identified from outpatient departments of Madinah Teaching Hospital, Mujahid Hospital, Inmotion Rehabilitation Clinic, and Jaffar Physiotherapy Clinic in Faisalabad, Pakistan. Flyers and physician referrals will be used. All interested individuals undergo a two-stage screening process:

Initial telephone screening: Age range, diagnosis of knee osteoarthritis, absence of obvious exclusion criteria.

In-person clinical screening: Confirmation of Grade III Kellgren-Lawrence radiograph (available within prior 12 months or newly obtained), DN-4 administration, physical examination, and review of medical history.

Randomization and Allocation Concealment

After providing informed consent and completing baseline assessments, eligible participants will be randomly assigned to either Group A or Group B in a 1:1 ratio. Randomization sequence will be generated using an online random number generator (Randomizer.org) with variable block sizes of 4 and 6. Allocation concealment will be maintained using sequentially numbered, opaque, sealed envelopes prepared by an investigator not involved in participant recruitment or outcome assessment.

Blinding

This is a double-blind trial:

Participant blinding: Participants are unaware of whether they receive pregabalin-encapsulated hydrogel or aqua gel. Both hydrogels are identical in appearance, viscosity, odor, and packaging.

Outcome assessor blinding: The assessor performing baseline and post-intervention measurements (NPRS, DN-4, WOMAC) will have no knowledge of group assignment and will not be present during treatment sessions.

Therapist blinding: Not possible, as the therapist prepares the gel and knows which is being applied. To minimize bias, therapists will follow a standardized script and avoid any verbal cues regarding expected outcomes.

Intervention Protocol Details

Common Procedures for Both Groups:

Each session lasts approximately 25-30 minutes and follows this sequence:

Hot pack application (10 minutes): Standard hydrocollator hot pack (temperature approximately 70°C, insulated with layers of toweling) applied to the posterior knee and upper calf to increase tissue temperature, blood flow, and muscle extensibility prior to MET.

Phonophoresis (5 minutes): The participant lies supine with the affected knee slightly flexed on a rolled towel for comfort. The therapist applies the assigned gel (pregabalin-encapsulated or aqua gel) to the medial, lateral, and posterior aspects of the knee joint. Ultrasound unit (Sonopuls 490, Enraf-Nonius) parameters: continuous mode, frequency 1 MHz, intensity 1 W/cm². The sound head (5 cm² effective radiating area) is moved in a slow circular motion (approximately 2-3 cm/sec) over an area twice the size of the sound head. Total treatment time: 5 minutes, including all three knee regions.

Gastrocnemius Muscle Energy Technique - Post-Isometric Relaxation (10-12 minutes):

Position: Supine, legs extended, ankle in neutral.

Therapist position: Standing at the foot of the treatment table on the side of the affected leg.

Grip: One hand stabilizes the distal femur just proximal to the knee joint; the other hand holds the plantar aspect of the foot with palmar contact.

Step 1 - Isometric contraction: Therapist instructs: "Push your foot down into my hand, like pointing your toe. Do not move - just push against me. Use about 25% of your maximum strength." Contraction held for 7-10 seconds. Therapist provides sufficient resistance to prevent any joint movement (true isometric).

Step 2 - Relaxation: Therapist instructs: "Now relax completely. Let me do the work."

Step 3 - Stretch phase: Immediately following relaxation, therapist passively dorsiflexes the ankle to stretch the gastrocnemius, moving to the first point of tissue resistance or until the participant reports mild stretch (never pain). The stretch is held for 10 seconds while maintaining knee extension.

Step 4 - Repeat: The cycle (contract-relax-stretch) is repeated 4-5 times per session.

• Change in Pain Intensity [Time frame: Baseline (week 0, pre-intervention) and Week 4 (post-intervention, after 16 sessions)]
• Change in Functional Mobility and Stiffness [Time frame: Baseline (week 0, pre-intervention) and Week 4 (post-intervention, after 16 sessions)]