Transdermal Therapy (TDT)

Transdermal Therapy (TDT)

Pain Physiology:

Pain receptor (Nociceptor) is stimulated by a painful stimulus and converts this sensation by process called transduction into electrical signal or action potential. The latter propagates through the afferent nerve into the next neuron in the pathway. Sodium and calcium channels are important for this action potential propagation. The nerve impulse ascends in the spinothalamic tracts to the thalamus and cortex where it is felt as pain sensation and emotional preception of pain as well autonomic reflexes to pain as hypertension, tachycardia, sweating, vagal and vasovagal responses.

Locally tissue injury cause white blood cells to release pro-inflammatory mediators many of them drived from Arachadonic acid pain pathway (AAPP) and inculde prostaglandins and cytokines. These substances irritate the nociceptors and cause them to fire at lower threshold of stimulus or even fire spontaneously. TNF or tissue necrosis factor is an example of these cytokines. Anti-TNF antibodies are used recentely by injections in patients with inflammatory conditions like rhumatoid,  etanercept is an example. Inflammation and injury also activate NMDA receptors (N-methyl-D-aspartate) resulting in more firing of these noceiceptors.

How TDT releive pain:
The main mechanisms of the chemicals in TDT work is through blocking the pain in one or more of the above main steps:

1- Blocking the pro-inflammatory mediators thus raising the threshold for pain or in other words decreasing their sensitization: examples of substances in TDT that serve the function of blocking AAPP are: Diclofenac, tranilast and pentoxifylline. Moreover tranilast block the TNF.

2- Blocking the ion channels in the ligand-gated ion channels of NMDA, examples: ketamine, amantadine and orphenadrine.

3- Blocking Sodium channels, examples: Bupivacaine, amitriptyline (also block other receptors)

4- Blocking calcium channnels, examples: nifedipine, verapamil

5- Blocking calcium channel through activation of GABBA receptors as: gabapentin (neurintin), pregabalin (lyrica) and baclofen.

What kinds of TDT and how it is delivered::
Basic cream and multi-agents according to condtion  with main substance as mentioned below.
Basic cream + diclofenac for inflammation
Basic cream + ketamine and amitryptaline for neuropathic pain
Basic cream + ketamine and diclfenac for deep muscle pain

Base cream: Pentoxifylline, magnesium and tranilast inhibit PGE2 and cytokines. MSM dervative of DMSO asssist transport of cream. Bromelain help the ingradients to dissolve into the cream. Diffusing agents as alochol and glycerin are used to help the diffusion of the cream. Versapro is a surfactant that has outward lipopophillic end and inward hydrophillic end that bind the hydrophillic medication. Thus the micelles or small balls pass through the stratum corneum and transmit the drugs and once deep in the skin they dissolve and serve as reservoir when applied several times a day.


TDT Uses and Benefits

TDT is used for both acute and chronic pains. Chronic pain: is pain after 3-6 months. It does not serve a function and it its a disorder itself. Though primary treament is commonly the solution like total knee replacement in more advanced OA disease, in most patients with chronic pain control is more important and is the ultimate treatment.
Examples of benefits and uses:

1- Most pain syndromes are musculoskeletal and superficial and amenable to TDT
2- TDT is effective in both acute and chronic pains.
TDT is Effective to most cases of chronic pain: Pain prevalence according to CDC:
low back 28%
neck 15%
knee joint 18%
shoulder 9%
Migraine 15%

3- TDT can be the sole medication used for pain or can be used with other medications and therapies for pain.
4- TDT can be used pre-sport or after-sport to muscles, tendons and joints known to patient to be vulnerable to post-exercise aggrevation.
5- TDT starts to work in minutes after application and pain control continue to increase due to the formation of reservoir locally as patients take the TDT regularly.
6- Less than 5% are absorped of TDT which make systemic effect or drug interaction much less likely and base line renal or hepatic function is not need to be checked prior to use.
7- The compounds in TDT work in pain receptors peripherally, opiates for example work centrally in the brain so it is associated commonly with depression of other brain centers and in higher doses can cause respiratory and cardiovascular depression.
8- About 16500 death yearly are due to NSAIDs and similar number of death is due to narcotics overdose. Using TDT is likely to drop these figures.
9- Multi-compounds delivered in one cream improve effectivenss and compliance. Compare that with the need to use different classes of oral medications to control the pain.
10- While most of medication for pain need to be titrated up slowly particularly narcotics and muscle relaxants, cympalta, lyrica and gabapentin TDT is applied from the start 3-4 times a day.
11- Dosing narcotics and NSAID less often with regular use of TDT can present to a good sector of patients more safe and effective control of pain. Example is NSAID's about one or twice a week for signifcant pain with PPI PRN another example vicodin twice a day with TDT.
12- Compared to main pain medication applied to the skin TDT has many mechanisms of actions. Head to head studies unlikely to be conducted. However the use of local therapy is the way of the future in pain cotrol. As a role I use TDT as my first line of therapy unless patient is already doing well on an over the counter cream or lidoderm patch. TDT is more likely to control deeper pain, neuropathic pain and muscle tension/spasms than other local treatment.  Examples to non-TDT local pain theraputics : Local anesthetics as Lidocaine patches. Also the non-steroidal anti-inflammatory drug diclofenac or aspirin creams, (Aspercreme, BenGay) Counter-irritants substances such as menthol, eucalyptus, or oil of wintergreen that irritate nerve endings, producing a "cool" feeling on the skin and distracting the brain from deeper sources of pain. Vicks VapoRub is an example of a counter-irritant as well capsaicin.

TDT Shortcomings
1- TDT is not effective in visceral pain
2- TDT is contraindicated for facial pain sydnromes.
3- TDT is less effective in spinal stenosis, spinal claudication, radicular pain or cord comperssion symptoms

though help with other therpies to alleviate the pain and can decrease use of narcotics, NSAIDs and Muscle relaxants. Thus it si still plays a major in spine diseases when surgery is unlikely to help or after failled back surgeries.
4- TDT is less effective in hip OA with pain mainly in the groin
5- TDT is not helpful or indicated for migraine headaches and other headaches but can be helpful for headaches related to tight posterior neck muscles.
6- TDT is used after diagonsis is secure a cause of pain is important particularly fractures, infections and cancers.

TDT is and important and likely to be quickly growing therapy for pain. Other therapies are likely to be needed possibly in lower does and lesser frequency along with TDT. Many skilled professionals are part of the pain management including any/all of the following:
neurologists/neurosurgeons
orthopaedists/orthopaedic surgeons
anesthesiologists
physiatrists
nurses
physical therapists
occupational therapists
psychologists/psychiatrists
Special pain programs are located in many hospitals, rehabilitation facilities, and pain clinics.

Summary:
TDT is a new breakthrough in pain control.
1- It is effective.
2- It works fast and continue to work with time.
3- It is safe.
4- Systemic absorption is very low and TDT works mainly locally where the pain is.
5- There is no significant tolerance to TDT.
6- No need to titration.
7- Easy to order. Sheet have the cream the doctor chose, demographics are filled and is faxed to the company. Sheets have the fax number. Between the doctor and his staff the process take only 5 minutes. Patient is contacted and insurance information is obtained and the pump is delivered to the patient home in about 1-3 days. Patient can also consult with the TDT pharmacist for change to another type of pump if the one he ordered did not work. Process is smoth and the company take most insurance and I never asked for prior authorization and if I am asked I am not going to do it.