Topical Menthol +/- Mannitol for Painful Diabetic Peripheral Neuropathy
Condition: Diabetic Peripheral Neuropathy
MeSH terms: Peripheral Nervous System Diseases; Diabetic Neuropathies
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Treatments for painful diabetic peripheral neuropathy (PDPN) are not very effective and have
      multiple side effects. To find out if a menthol cream alone or with added mannitol treats
      PDPN effectively, 90 participants with PDPN, after one month of observation, will receive
      randomly assigned menthol cream or the same cream with mannitol added for 3 months with a
      crossover for 3 additional months. At time 0, 1,4 and 7 months their BPI pain severity and
      interference scores, DN4 scores, cream % effectiveness and side effects will be compared.
    

Detailed description: 
      Purpose: to find out if a menthol cream containing mannitol is more effective than the same
      cream without mannitol in relieving painful diabetic peripheral neuropathy (PDPN). The test
      cream which will, at a later date, be marketed as QR cream contains Water, Mannitol,
      Propylene glycol, Isopropyl palmitate. Caprylic capric triglyceride, Ceteareth 20, Cetearyl
      alcohol, Glyceryl stearate, Polyethylene glycol 100 Stearate, Dimethicone, Octyldodecanol,
      Menthol, Lecithin, Ethylhexyl glycerin, Phenoxyethanol. The control cream contains the same
      ingredients minus the mannitol.

      Hypothesis: a menthol cream containing mannitol is more effective at relieving the pain, the
      physical limitations and the emotional distress caused by PDPN than the same cream without
      mannitol.

      Justification: PDPN is common and can be disabling because of the intensity of the pain it
      can cause. Less than 50% of those suffering from this condition get adequate pain relief from
      their current medications. The oral medications, anticonvulsants, antidepressants, NSAIDS,
      marijuana derivatives and narcotics have numerous side effects and are potentially addictive.
      Topical local anaesthetics have short-lived effect over only a small area and topical
      capsaicin often causes burning on application and prolonged use destroys the affected nerves.
      A previous study has demonstrated mannitol's effectiveness in down regulating the capsaicin
      receptor which is believed to cause the burning sensation of PDPN. A cream containing
      mannitol has few side effects, and, if effective, may decrease the need for other, more
      dangerous medications.

      Objectives: to show that a menthol cream containing mannitol is more effective, over a period
      of 28 weeks, than the same cream without mannitol at relieving the pain, the physical
      limitations and the emotional distress caused by PDPN.

      Research Design: this is a randomized, double-blind, placebo-controlled crossover trial
      involving 3 visits.

      Participants who are taking medications or insulin to treat diabetes will have on/off
      vibration test on the hallux of each foot. If at least 5 of their 8 vibration tests are
      erroneous or "I don't know", their score on the DN4 questionnaire is >4/10 they will be
      enrolled.

      After 1 month's observation period, 90 participants will be given either a menthol cream with
      mannitol or the same cream without mannitol to apply to their feet for 3 months, following
      which the creams will be crossed over for an additional 3 months. Which cream is to be
      applied in the first 3 months will be chosen at random. Participants and clinicians will be
      blinded as to cream assignment for the duration of the study. Participants will be instructed
      to rub the cream on their feet and the tender nerves supplying their feet, 2 to 4 times
      daily, as needed for pain relief.

      At 0,1,4 and 7 month, their BPI pain severity and interference scores, DN4 scores, cream %
      effectiveness and side effects will be recorded. At 4 and 7 months, they will be compared.

      Statistical Analysis: primary endpoint, BPI pain interference scores (how much pain
      interferes with function and relationships) . t-tests will compare the difference between the
      maximum daily pain interference score for the menthol cream as compared with the mannitol and
      menthol cream at 4 and 7 months. Secondary endpoints: BPI pain severity score and DN4 score
      (how many symptoms of peripheral neuropathy are registered), % cream effectiveness, incidence
      of side effects.
    

Intervention name(s): Mannitol; Menthol
Intervention type(s): Drug; Drug
Intervention description(s): Apply cream as needed up to 4 times daily to the painful foot and leg; Apply cream as needed up to 4 times daily to the painful foot and leg
Other intervention name(s): QR cream
Intervention MeSH terms: Mannitol; Menthol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: peripheral neuropathy; Diabetes; Pain