Accurate Education - Topical Medications For Pain

Topical Medications for Pain

“Foolish is the doctor who despises the knowledge acquired by the ancients.” — Hippocrates

Topically applied medications are important treatment options for those with both acute and chronic pain. The world of topical pain medications is complex and can be daunting for the uninformed, especially when selecting an over-the-counter (OTC) product. This section provides the information needed to make informed decisions regarding OTC products as well as providing insight as to prescription medications recommended by a clinician.

Link to videos on this topic on Dr. Ehlenberger’s Youtube channel:

@EricEhlenbergerMD

Links to other Pertinent Educational Pages:

Commercial Topical Medications Products:

Key to Links:

Grey text – handout
Red text – another page on this website
Blue text – Journal publication

Links to topical medications by condition:

Topicals for Acute & Chronic Muscle Pain
Topicals for Arthritis
Topicals for Neuropathic Pain

OTC Watch: Always review the ingredients in topical medications. Many, if not most, of the well-known brand name topical medications have multiple products that each may have different ingredients where some may contain lidocaine, diclofenac, salicylates, menthol and camphor. Some products may also include additional ingredients such as herbal extracts.

Topically Applied Medications

To begin, medications designed to be applied topically to the skin for therapeutic purposes are generally referred to as “topicals.” Technically, however, topically applied medications may be either “transdermal” or “topical.” The distinction is quite important and determines the therapeutic impact of the product. This web section focuses only on topical medications for pain.

Transdermal vs Topical

Transdermalmedications are designed to penetrate the skin barrier in order to enter the blood and provide systemic (whole body) benefits. By penetrating through the epidermis, the topmost layers of the skin, and into the underlying dermis layer where the blood vessels are, transdermal products enter the blood vessels and are then transported through the blood to the organs, including the central nervous system (spinal cord and brain) to provide therapeutic benefits.

Topicalformulations, on the other hand, refers to creams, lotions, ointments, and other products designed to be applied to the skin (epidermis) to permeate (travel) through the skin to act regionally (e.g., for the treatment of muscle or join pain) for local therapeutic benefits only. They are not formulated to transport medications into the blood vessels of the subcutaeous dermal layer below and therefore are not meant to enter systemic circulation for the treatment of symptoms at sites a distance away.

Due to the wide variety of medical conditions associated with pain, the selection of an appropriated topical pain medication requires an understanding of the underlying mechanism(s) underlying both the pain and the medications potentially available to treat that pain.

Topically Applied vs Orally Ingested Medications

An important point to emphasize is that some medications, notably diclofenac, achieve significantly higher levels in muscle and joint (synovial) tissue when applied topically vs when taken orally. This suggests that a topical medication is likely to work better than an oral version although studies identify a similar pain response. Furthermore, because blood (serum) levels are much lower (@1%) than with topical medications, there is far less toxicity and side effects, especially gastrointestinal, when medications are applied topically. This is particularly of value with the NSAIDs class of medications.

In a 2010 study, systemic bioavailability and pharmacodynamics of topical diclofenac sodium gel 1% were compared with those of oral diclofenac sodium 50-mg tablets. In a randomized, 3-way crossover study, 40 healthy volunteers received three 7-day diclofenac regimens:

16 g gel applied as 4 g to 1 knee 4 times daily (4 g on surface area 400 cm(2)),
48 g gel applied as 4 g per knee 4 times daily to 2 knees plus 2 g gel per hand applied 4 times daily to 2 hands (12 g on 1200 cm(2)), and
150 mg oral diclofenac applied as 50-mg tablets 3 times daily.

Results:

- Systemic exposure was greater with oral diclofenac (AUC(0-24), 3890 +/- 1710 ng x h/mL) than with topical treatments A (AUC(0-24), 233 +/- 128 ng x h/mL) and B (AUC(0-24), 807 +/- 478 ng x h/mL).
- Oral diclofenac inhibited platelet aggregation, cyclooxygenase-1 (COX-1), and COX-2.
- Topical diclofenac did not inhibit platelet aggregation and inhibited COX-1 and COX-2 less than oral diclofenac.
- Treatment-related adverse events were mild and limited to application site reactions with diclofenac sodium gel 1% (n = 4) and gastrointestinal reactions with oral diclofenac (n = 3).
- Systemic exposure with diclofenac sodium gel 1% was 5- to 17-fold lower than with oral diclofenac.
- Systemic effects with topical diclofenac were less pronounced.

Where to Start?

For those simply looking for where to start, this section will guide you.

For more in-depth exploration of individual medications and their indications, move forward to the next section below and explore Topical Medications for Pain – Synergy

In general, start with inexpensive but effective topical medications first. Since insurance often pays for only the prescription topicals lidocaine and diclofenac, one should start with either lidocaine or diclofenac first to determine their individual benefits then try the two together to determined their combined benefit.

It should be noted that simultaneous use of a topical menthol product such as Biofreeze or Icy Hot can enhance the absorption of the diclofenac resulting in greater pain benefits although possible greater local. skin side effects.

Unfortunately, the other prescription topical medications effective for pain are not usually covered by insurance and are relatively expensive, so the next less-expensive topicals to add are OTC products with CBD, BCP and/or PEA. There are tw0 products providing a different two of these three:

CBD/BCP (AliceCBD.com): This combination adds both CBD and BCP
Soothe” (BCP/PEA) (TullaBotanicals.com): This combination adds both BCP and PEA

After adding one of these products and determining its benefit, try the other to determinne its benefit and onsider implementing the better of the two into your regimen. The next step if desired is to identify and add. the the missing element, either CBD or PEA depending on the product you preferred.

Following this regiment you may find the combination of lidocaine, diclofenac and BCP along with PEA and/or CBD to be your best. But if you wish to explore further, the next steps would include exploring diffferent prescription medications that can be compounded by a special compounding pharmacy. Sometmes compounded medications can be covered by insurance. The following compounded medications should be considered, especially for neuropathic pain such as peripheral neuropathies:

Gabapentin
Ketamine
Amitriptyline
Clonidine

Additional alternative topical medications offering potential pain benefits are reviewed below.

Medical conditions that may respond to topical medications include:

Acute & Chronic Muscle Pain (sore muscles and trigger points, Sprains and Tendonitis)
Arthritis (joints) & Bursitis
Neuropathic Pain (diabetic, Ehler-Danlos, Multiple Sclerosis, post-radiation, polyneuropathy, Fibromyalgia)

1. Acute & Chronic Muscle Pain (sore muscles and trigger points), Sprains and Tendonitis

Acute muscle pain may arise from tissue damage from trauma or overuse and may include an inflammatory component. Therefore a topical medication with anti-inflammatory properties and analgesic benefits would be recommended. However, a neuropathic pain component should be anticipated as well when circumstances suggest the tissue pain potentially to be transitioning from acute to chronic pain (>>3 months) or it has already transitioned as in the case with trigger points. This transition is driven by neuro-inflammation and oxidative stress and therefore topical medications to suppress the development of neuro-inflammation would be advised. Such topicals should include anti-inflammatory, antioxidant and neuropathic agents.

The following topical medications are recommended for muscle, sprain and tendonitis pain:

Diclofenac gel 1% (OTC or Rx); or 3%) (Rx)
Topical CBD, BCP and/or THC cream (OTC/Rx) including combination CBD/BCP and BCP/PEA)
Lidocaine: cream (OTC or Rx) or
Lidocaine: patches (OTC; Lidoderm 5% or ZTLido patches (Rx)
Topical Palmitoylethanolamide PEA (OTC)
Topical Baclofen 6% (Rx/Compounded)
Topical Gabapentin 6% (Rx/Compounded)
Menthol (OTC: products such as Biofreeze)
Magnesium (creams and/or Epsom salt baths)

Priority of choice is largely dependent on financial considerations and insurance coverage. Since the mechanisms of action of each of these medications are all different, they can be used simultaneously on the same day but not necessarily applied together.

2. Arthritis (Degenerative or Osteoarthrits and Rheumatoid Arthritis)

Osteoarthritis & Bursitis

The term arthritis is typically applied to osteoarthritis or degenerative arthritis, the arthritis associated mostly with aging. It is a condition that does have an inflammatory component, but also has a significant neuropathic component (nerve pain). Therefore topical medications directed at inflammation as well as those directed at nerve pain would be expected to benefit someone with osteoarthritis. Bursitis is an inflammatory condition involving joint structures called bursa. A bursa is a closed, fluid-filled sac located next to tendons near large joints and functions as a cushion and gliding surface. Bursitis would be expected to respond to the same topical medications as arthritis with emphasis on the NSAIDs.

The following topical medications are recommended for osteoarthritis and bursitis pain:

Topical Diclofenac gel 1% (OTC or Rx); or 3%) (Rx)
Topical CBD, BCP and/or THC cream (OTC/Rx) including combinations CBD/BCP and BCP/PEA)
Topical Lidocaine cream (OTC or Rx),
Lidoderm 4% patches (OTC), 5% patches(Rx) or ZTLido patches (Rx)
Topical palmitoylethanolamide PEA (OTC)
Topical Gabapentin 6% (Compounded)

Rheumatoid Arthritis

In the case of rheumatoid arthritis and other immune related, arthritis is such as those associated with psoriasis or lupus, there is a dominant component of inflammation, underlying the disease process, and therefore these conditions would benefit most from anti-inflammatory topical medication (NSAID or steroid). The strongest anti-inflammatory, topical medication’s are steroids, such as dexamethasone and Cortisone. However, steroid medication’s have the potential for toxicity or detrimental effects, so treatment with topical steroids should generally be prescribed by rheumatologists or other physicians with specific expertise to avoid complications.

The following topicals are recommended for rheumatoid arthritis pain:

Diclofenac gel 1% (OTC or Rx); or 3%) (Rx)
Topical CBD, BCP and/or THC cream (OTC/Rx) including combinations CBD/BCP and BCP/PEA)
Topical Lidocaine: cream (OTC and/or Rx) or patches (OTC; Lidoderm 5% or ZTLido patches (Rx)
Topical PEA (palmitoylethanolamide) cream (OTC)
Topical Compounded Gabapentin 6%
Corticosteroids as advised by a rheumatologist

Priority of choice is largely dependent on financial considerations and insurance coverage. Since the mechanisms of action of each of these medications is different, they can be used simultaneously on the same day but not necessarily applied together.

3. Neuropathic Pain – Neuropathy, Fibromyalgia, Carpal Tunnel Syndrome

Neuropathic pain may be a significant component of various conditions, not typically thought of as based on pathology of the nervous system, such as arthritis, headaches, and visceral pain, it is the dominant contributor to the pain associated with conditions, such as diabetic peripheral neuropathy, chemotherapy induced neuropathy, post-herpetic neuropathy,and various polyneuropathies and mononeuropathies related to peripheral nerve compression syndrome, such as carpal tunnel syndrome. Also included in pain conditions based in neuropathic pain are fibromyalgia and chronic regional pain syndrome amongst others. For the most part, these conditions have not demonstrated significant benefit from the application of topical NSAID medications.

The following topical medications are recommended for neuropathic pain:

Topical Lidocaine: cream (OTC or Rx) or patches (OTC; Lidoderm 5% or ZTLido patches (Rx)
Topical CBD, BCP and/or THC cream (OTC/Rx) including combinations CBD/BCP and BCP/PEA)
Topical Gabapentin 6% (Compounded)
Topical PEA (palmitoylethanolamide) cream (OTC)
Topical Baclofen 6% (Compounded)
Capsaicin 8% patches (Rx)

Capsaicin

Capsaicin is a compound derived from chili peppers that has analgesic properties. It is used as a homeopathic remedy counter-irritantnto treat burning pain using the concept of “treating like with like.” It is available in many OTC products at strengths ranging from 0-25-0.75% and as an 8% prescription medication.

Mechanism of Action:

Capsaicin binds to nerve endings in the skin (cutaneous pain receptors or nociceptors) to activates the transient receptor potential vanilloid 1 (TRVP1) pain receptor. Repeated applications or high concentrations provide pain relief due to reduction in activity of TRPV1 c by depleting their chemical stores.

OTC Capsaicin

Effectiveness:

While approximately half the time patients using OTC products obtain significant benefit at 4 weeks of application, half or more users experience side effects that often drive discontinuation of use. OTC capsaicin is not generally recommemded by arthritis experts.

Side Effects:

Application of capsaicin causes an initial burning sensation along with redness of the skin that often persists.

Capsaicin 8% (Qutenza) patches (Rx)

Prescription 8% (Qutenza) patches are applied by clinicians in their office every 30 days. Up to four patches are placed applied to the painful areas after pre-treatment with local anesthetic and left in place for 30 minutes (feet) to 60 minutes (other areas). Conditions treated include painful diabetic neuropathy and post-herpetic neuralgia.

Effectiveness:

Approximately 30% or more patient achieve at least 50% reduction in their pain, although a full response may require a minimum of two treatments

Side Effects:

Application of the 8% capsaicin are generally well tolerated, particularly in painful diabetic neuropathy due to the destruction of small fiber nerves associated with the disease.

Natural, Plant-Based Compounds

Terpenes: (BCP, Linalool)

Terpenes are fragrant chemicals found in many plants and spices. They may serve two functions when applied topically: they may provide an enhanced carrier function to other constituents with which they are applied, including CBD. Additionally, some terpenes offer their own therapeutic benefits, particularly β-caryophyllene.

For information regarding specific terpenes, see below:

Arnica

Arnica belongs to the Asteraceae family, a group of flowering plants containing several well-known members, such as marigold, daisy, and chamomile. Arnica has been used in traditional medicines for centuries in Europe and North America and has been used in homeopathic medicine for dozens of pathological conditions, including joint and muscle pain, inflammation, and arthritis. It has been proposed to have various therapeutic properties, including anti-inflammatory, analgesic, anti-microbial, anti-rheumatic, antiarthritic, and antineoplastic activities.

There are several forms of homeopathic arnica commercial products, including gels, creams, roll-ons, teas, pellets, liquids, and tablets but topical preparations are the most commonly used. These products are widely available in retail pharmacies ranging in strengths.

Effectiveness

Arnica offers comparable benefits to topical NSAID medications such as ibuprofen and diclofenac for pain with different medical conditions including post-traumatic ankle sprains, tendinitis, arthritis and chronic low back pain. It also has fewer adverse effects along with lower costs. In a 2013 Cochrane review, arnica gel was reported to be non-inferior to topical ibuprofen and “probably improves pain and function as well as topical NSAID drugs do …with no better (and possibly worse) adverse event profile.”

Safety

In clinical trials, adverse skin reactions have been reported with topical arnica. Contact dermatitis can develop, resulting in a rash, itching, and dry skin. Allergic reactions with topical arnica are cross-reactive with plants in the Compositae and Asteraceae families.

Mechanisms of Action

It is not clear as to how specifically arnica works on pain but it involves inhibitory activity on the expression of TNF-α, IL-1β, IL-6, and IL-12.

Frankincense (Boswellia serrate)

Indian frankincense is a plant extract used in Ayurvedic medicine as a remedy to treat inflammation and pain and a number of diseases. Frankincense is a natural product of Boswellia trees and oil and water extracts have long been used topically.

Effectiveness

Of interest are case reports of individuals with long-standing, debilitating benign essential blepharospasm (spasm of eyelids) achieving significant symptom relief after regular use of topical frankincense essential oil. Topical frankincense appears to offers an effective treatment option for this chronic, progressive condition.

Taken orally frankincense reduces inflammation in joints to aid in arthritis pain but definitive evidence is lacking for its benefit when applied topically. In the first randomized, double blind, placebo controlled study of topical frankincence for knee osteoarthritis, a 2023 study demonstrated decreased pain severity and stiffness of the knee and improved daily activity.

Mechanisms of action

Boswellic acids present in frankincense resin reduce inflammation by inhibiting 5-lipoxigenase enzyme as well as NF-ĸB (nuclear factor kappa B) and TNF-α (tumor necrosis factor in many inflammatory pathways. Additionally, findings suggest that topical application of frankincense with its active ingredients (including the terpenes α-pinene, linalool, and 1-octanol) have significant anti-inflammatory and analgesic benefits by inhibiting cyclooxygenase-2 (COX-2), in a similar mechanism by which NSAIDs such as ibuprofen and naproxen work.

Compounded Topical Medications

Based on a Cochrane review published recently in 2020 (Compounded Topical Pain Creams- Review of Select Ingredients for Safety, Effectiveness, and Use (2020)):

In most if not all cases there is simply inadequate research to provide definitive conclusions regarding the effectiveness of the medications reviewed. Additional research is needed to determine the effectiveness of all these medications. However, when topically applied appropriately, there are no significant safety concerns for any of the medications described here other than local skin irritation. Importantly, however, the absence of safety data does not prove safety or indicate that adverse events have not occurred. Indiscriminate use over large skin areas or use on non-intact skin can have safety concerns. Typically a large percentage of the time, when a product or medication cannot be patented there is a lack of meaningful research.

Key Definitions

Creams: A semisolid oil-in-water emulsion for application to the skin. Creams are spreadable and easily rub into the skin without a greasy residue, and can be washed off with water.
Excipient: A pharmacologically inactive ingredient used in the formulation of a drug that lends various functional properties to the drug formulation (i.e., dosage form, drug release, etc.). They are also sometimes referred to as diluents, bases, or carriers and can sometimes increase absorption of active ingredients.
Gels: Also referred to as jellies, gels are a semi-solid dosage form that appears transparent or translucent and employs either a hydrophobic or hydrophilic base.
Lotions: While similar to a cream, lotions have a more liquid consistency. The lower viscosity may provide a cooling effect to the area where applied when solvents in the lotion evaporate.
Ointments: A semi-solid preparation with four general classes ranging from occlusive, hard to remove hydrocarbon bases, to easily washable water soluble bases.
Penetration enhancer: An excipient or vehicle that aids in absorption of ingredients through the skin.
Vehicles: A component that is used as a carrier or diluent in which liquids, semi-solids, or solids are dissolved or suspended.

The Terms Effectiveness and Efficacy

When reading any of the journal articles listed below, one will encounter the terms Effectiveness and Efficacy. While similar, the terms are not synonymous. Efficacy refers to the therapeutic effect of a treatment under controlled conditions, while effectiveness refers to the therapeutic effect in “real-world” situations in which certain contextual measures (e.g., placebo effect) may not be strictly controlled and broad outcome measures (e.g., health-related quality of life) are considered.

Non-Steroid Anti-inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase enzyme to reduce inflammation and pain. Compared with oral formulations, topical NSAIDs work only locally (when limited to concentations < 5%. Studies have shown that topical NSAIDs provided similar pain relief to oral NSAIDs for patients with chronic osteoarthritis and for patients with acute musculoskeletal pain. High-quality evidence supports the analgesic benefit of several topical NSAIDs, including diclofenac and ketoprofen. Some OTC formulations include methyl salicylate or other salicylates that are chemically related to aspirin and may also be found in herbal based products including willow bark. There is little definitive evidence for salicylates effectiveness but they are commonly used especially in traditional and folk remedies.

Systematic reviews of placebo-controlled randomized controlled trials confirm the effectiveness of several topical NSAIDs in treating pain from soft tissue injuries and chronic osteoarthritis. For acute sprains and strains, topical diclofenac and ketoprofen improved pain by 50% from baseline within 1 week. For chronic hand and knee osteoarthritis, topical diclofenac and ketoprofen improved pain by 50% within 6 weeks.

Topical NSAIDs are safer than oral NSAIDs by avoiding the risks of gastritis, G.I. bleeding, injury to kidneys or liver and risk of cardiovascular complications. Common adverse events from topical agents are mild and include local skin reactions (e.g., dry skin) and itching).

Naproxen

Naproxen has been used in compounded formulations, but no evidence is available that it is superior to topical diclofenac. Since topical diclofenac is available both by prescription and over-the-counter, compounding with naproxen is not generally recommended in favor of diclofenac.

Effectiveness:

There is limited and inconsistent evidence to suggest that naproxen (1–10 percent gel) is effective to treat pain related to soft tissue injuries. A double- blinded, randomized study that compared 10 percent naproxen gel and a placebo in 120 patients with soft tissue injuries (mostly synovitis and tendinitis) did find the naproxen gel significantly reduced pain.

Dermal penetration/bioavailability:

One study compared topical application of naproxen topical application of 1 percent naproxen sodium gel prepared without penetration enhancers. Compared to oral administration of sodium naproxen tablets, topical application showed significantly lower maximum blood concentration, similar time to reach the peak blood concentration, earlier terminal elimination half- life (1 hour sooner), but higher area under the curve (total exposure time.

Unfortunately, no studies are available that evaluate the intra-articular joint levels of naproxen resulting from topical versus oral administration of the drug.

Safety and adverse effects:

Topical naproxen may be associated with skin irritation and itching.

Neuropathic Agents:

Clonidine

Clonidine has been in clinical use for over 40 years, initially for treatment of hypertension, but later shown to be effective for treatment of acute and chronic pain. Clonidine ihas been described as an extremely potent pain medication with potency equal to or greater than that of morphine when used to treat acute and chronic pain intravenously or into the spine. However, systemic use of clonidine is limited by significant side effects including sedation, dry mouth, low blood pressure, and rebound hypertension.

Topical forms of clonidine are used to limit side effects but obtain analgesic benefits. Clonidine is lipophilic and easily penetrates the skin to reach the local pain pathways. The half-life of clonidine is about eight hours, thus it should be applied three times daily. Clonidine must be prepared by compounding pharmacies because no commercial preparation is available.

Effectiveness

Several animal and some human studies have shown that topical clonidine is an effective analgesic forf neuropathic pain but not likely for postoperative or inflammatory pain. A Cochrane review published in 2022 concluded “that a higher percentage of adults with painful diabetic neuropathy (PDN) may achieve pain relief of 30% or greater when treated with topical clonidine ( compared with placebo (48% versus 36%); however, the evidence for this outcome is very uncertain. Eight more people would have to be treated with topical clonidine compared to placebo for one more person to achieve moderate benefit. As such, topical clonidine used as a compounded cream may be recommended for peripheral neuropathic pain, probably in combination with other agents such as gabapentin or ketamine for someone with neuropathic pain otherwise resistant to more commonly recommended agents.

How clonidine works

Clonidine is a presynaptic alpha-2-adrenergic receptor agonist and targets receptors located in the brain, spinal cord, and dorsal root ganglia and on sensory neurons.

Gabapentin

Gabapentin (Neurontin) along with pregabalin (Lyrica) is one of the gold standard treatments for neuropathic pain. Evidence of benefit with oral use of gabapentin is quite good although not everybody does respond and it is not tolerated by some due to drowsiness or other side effects. Evidence for topical gabapentin is scarce, but nevertheless there is evidence to support topical use and safety.

Effectiveness:

Randomized controlled trials There are no relevant RCTs that examine the single-drug use of gabapentin in compounded topical creams to treat pain when applied to intact skin. However, a published case series in patients with mixed neuropathic pain reported benefit in 20 of 23 patients when treated with gabapentin 6% topically applied three times per day. Eleven of 23 patients reported at least 30 percent pain reduction, and 2 of 3 patients with postherpetic neuralgia reported reduction in pain by 60 percent and 57 percent..

Dermal penetration/bioavailability:

Evidence demonstrates that topical gabapentin can be detected at low concentrations in urine confirming that topical gabapentin penetrates the skin but the absorption varies greatly with the excipient used.Studies of urine concentration in patients exposed to topical gabapentin suggest very low to undetectable absorption rates.In patients taking oral gabapentin, average urine concentration levels are greater than 10,000 ng/mL. In contrast, in patients using topical gabapentin, average concentrations are 261 ng/mL.

Penetration enhancers:

Studies showed that gabapentin 6% with Carbopol hydrogels containing dimethyl sulfoxide (DMSO) or 70% ethanol, and a compounded gabapentin 10 percent in Lipoderm formulation, were able to facilitate permeation of the gabapentin molecule across human skin. Another study demonstrated formulations compounded using Lipoderm and Lipoderm ActiveMax enhancerss were able to permeate skin.

Safety and adverse effects:

There is insufficient evidence to determine the safety of topical gabapentin. However, if systemic absorption to therapeutic levels is achieved through topical application, there is potential for side effects similar to other routes of administration (e.g., oral). That being said, topical application is not likely to allow for therapeutic blood levels based on the urinary concentration data noted above as well as the rare, if any, complaints of systemic side effects reported.

Ketamine

Ketamine is a medication, gaining much attention in the recent times largely for it’s affective Ness with severe depression, but also regarding its effectiveness for neuropathic pain when used intravenously. Evidence for benefit with topical ketamine remains limited, but when doses are maintained as recommended, there appears to be very few side effects. There is off label use of ketamine delivered by nasal spray which is also getting some attention but research is lacking as to its benefits and safety.

Effectiveness:

There is mixed evidence regarding topical ketamine, some indicating that it is not superior to placebo for conditions including postherpetic neuralgia, complex regional pain syndrome (types I and II), painful diabetic neuropathy, and other types of neuropathic pain. Other trials suggest that topical ketamine in 5-10% gel may reduce pain in diabetic neuropathy and neuropathic pain associated with spinal cord injury and it may reduce allodynia in complex regional pain syndrome.

In a case of a 72-year-old woman with with CRPS I and severe pain, swelling, and a poor quality of life was treated with ketamine 10% cream and PEA (palmitoylethanolamide) capsules. The swelling improved, and the patient was more mobile at 1 month and continued to improve at 2 months.

Dermal penetration/bioavailability:

Topical ketamine can penetrate human skin. Serum concentrations of ketamine and its metabolite norketamine have been detected following topical use, although far below therapeutic concentrations. Modifications to the ingredient or excipient may increase absorption.

Safety and adverse effects:

Limited evidence suggests that topical ketamine is associated with minimal adverse effects after therapeutic application. Application of excessive amounts of ketamine containing topical products can lead to significant altered mental status and seizures. In a case report, a 35-year-old man who applied excessive amounts of a topical pain cream containing ketamine, baclofen, amitriptyline, lidocaine, and ketoprofen presented to the hospital unresponsive after a seizure.

Antispasmodic Agents:

Baclofen

There are insufficient studies to provide evidence on the effectiveness of topical baclofen to treat pain when applied to intact skin. However, there are case reports supporting its benefit and safety.

Muscle Spasm

Oral and topical baclofen is FDA approved to treat reversible muscle spasticity. Baclofen is thought to be primarily a centrally acting drug, is a structural analogue of GABA, and an agonist of GABAB receptors in the CNS with the greatest density in the dorsal horn of the spinal cord. By binding to these receptors, synaptic spinal reflexes are inhibited, thus reducing muscle tone and especially flexor spasms.

Pain

Evidence from animal studies suggests that baclofen may have a peripheral analgesic effect also. A case report describing a 65-year-old woman with neuropathic pain in her legs reported as 9 on a 0–10 scale. She was initially treated with a compounded analgesic cream, based on baclofen 5 percent and advised to apply 1 gram maximally three times per day. After 2 weeks, she reported reduction of her pain by more than 95 percent based on one application daily, but she complained of numbness in her legs. The dose was reduced to baclofen 2 percent, and she reported benefits with use only 1–3 times per week for 6 months without side effects.

Another case report describes a 54-year-old woman with neuropathic pain in both feet reported as 8 out of 10 on the NRS following chemotherapy treatment despite being prescribed oral gabapentin 2,000 mg daily and oxycodone 20 to 30 mg daily. Pain was reduced to 3 by a test application of compounded topical baclofen 5% cream,

Antidepressant Agents:

Amitriptyline

Amitriptyline taken orally has long been recommended for treating neuropathic pain and is considered in some recommendations to be a first level treatment. More recent studies have offered little support for its pain benefit taken orally and side effects include dry mouth and drowsiness are not uncommon. In fact, amitriptyline is commonly prescribed for night time use for insomnia.

Effectiveness:

There is limited evidence to suggest that topical amitriptyline is effective to treat neuropathic pain when applied to intact skin. Case reports demonstrate amitriptyline (5% and 10%) is effective with neuropathic pain in the hands and feet where all patients noted partial relief with the 5% cream and almost complete relief with the 10% cream. Two patients reported tiredness & drowsiness with 10% cream.

Dermal penetration/bioavailability:

Limited evidence suggests that a minimal amount of topically applied amitriptyline penetrates through human skin. Serum concentrations of topical amitriptyline have been detected at very low levels following topical use. A 62-year-old woman with pain in the upper arms and left foot attributable to multiple sclerosis was prescribed 5% amitriptyline cream applied to the upper forearms that resulted in decreased pain in the foot and upper arms after several minutes delay.

Safety and adverse effects:

Topical amitriptyline is associated with minimal adverse effects such as skin irritation, dryness, itching and redness, and drowsiness.

Mechanism of Action

Oral amitriptyline is an FDA-approved tricyclic antidepressant that was originally developed as a mood-regulating agent. It is thought to work by inhibiting the reuptake of norepinephrine and serotonin by presynaptic neuronal membranes in the CNS. At the spinal cord, amitriptyline exhibits ion-channel blocking effects on sodium, potassium, and NMDA channels. Norepinephrine, and sodium and NMDA channels, are involved in maintenance of some types of neuropathic pain. Off-label use of the oral formulation has been found to consistently reduce neuropathic forms of pain to a greater degree than comparison placebo groups.

Doxepin

Doxepin, like amitriptyline, is an oral antidepressant medication frequently prescribed for night time use for insomnia. However, also like amitriptyline, it is

Effectiveness:

There is limited evidence to suggest that topical doxepin may be effective to treat chronic neuropathic pain when administered at 3.3 percent concentration as an aqueous cream on intact skin. A case report showed that a 32-year-old female patient with complex regional pain syndrome type 1 resulting from a wrist injury experienced significantly reduced pain after 2 weeks of twice-daily topical application of doxepin cream.

Dermal penetration/bioavailability:

There is limited evidence to suggest that topical doxepin penetrates through human skin. One preclinical study detected serum concentrations that overlap with therapeutic concentrations (reported as 30–150 ng/mL).

Safety and adverse effects:

Evidence supports that topical doxepin is associated with minimal adverse effects. One clinical study determined potential effects include local stinging or burning, drowsi ness, headache, rash, and itching/allergic contact dermatitis. Drowsiness may be caused by systemic absorption.

Mechanism of Action

Doxepin is an FDA-approved psychotherapeutic agent (oral, topical) from the class of dibenzoxepin tricyclic compounds. The mechanism of action of doxepin has not been confirmed. The current understanding is that doxepin prevents reuptake of norepinephrine into nerve terminals by influencing activity in the synapse; this allows neurotransmitter activity to be prolonged. Norepinephrine is thought to be involved in the maintenance of some types of neuropathic pain, and this provides a rationale for off- label use of doxepin to treat certain types of pain.

Others

Ambroxol

Ambroxol is a drug with several properties including potent local anesthetic and anti-inflammatory activity. It has been studied in patients with neuropathic pain, including trigeminal neuralgia, and has shown good pain relief following topical application of 20% ambroxol cream. In a case series of CRPS patients, topical 20% ambroxol reduced spontaneous pain, edema, allodynia, hyperalgesia, and skin reddening and improved motor dysfunction and skin temperature. The evidence for topical ambroxol in neuropathic pain remains limited but it might be beneficial in some patients with localized neuropathic pain.

Mechanism of Action

Ambroxol is a very potent sodium channel (Nav) blocker, approximately 40 times stronger than lidocaine, and probably preferentially blocks the subtype Nav1.8, which is responsible for repetitive firing and neuronal excitability.

Compounded Drug Combinations

In Dr. Ehlenberger’s experience prescribing a compounded, topical cream containing amitriptyline, baclofen, diclofenac, gabapentin, ketamine and lidocaine over the last 15 years, he found a significant number of patients who experience meaningful pain relief from its use, often intermittently.

Case report described significant pain relief with a combination gel with gabapentin 6%/amitriptyline 2%/lidocaine 5%/ ketoprofen 10% in a patient following gall bladder surgery. There are multiple case reports of various combinations of topical medications demonstrating pain benefits but no gold standard double blinded, random controlled trials to offer definitive evidence of benefit.

Compounded Three-Drug Combinations: Ketamine, Amitriptyline, and Lidocaine

Effectiveness

Clinical studies: A 1% ketamine/2% amitriptyline/5% lidocaine gel was evaluated in 16 patients with neuropathic pain from radiation-induced dermatitis. Patients applied ~4 mL to the painful areas three times daily until 2 weeks after completion of radiotherapy. A reduction in scores for intensity, sharpness, burning, sensitivity, unpleasantness, and deepness was found 30 minutes after application and the reduction in burning was maintained for 2 weeks posttreatment.

Traditional Chinese Topical Medications

It should be noted that the traditional Chinese system of medicine (TCM) is based on completely different principles and understanding of health and disease. In TCM health becomes impaired related to the proper balance of flow of “chi.” the life energy that flows through meridians distributed throughout the body. This inherent difference in understanding disease states starts with different diagnostic approache and completely different treatment approaches not based on the western principles of anatomy and physiology.

Consequently one cannot simply establish a diagnosis based on western principles of diagnostio evaluation then proceed to select a TCM medication for treatment. It simply does not work that way. As with any medical systtem, the success of treatment is based on the accuracy of diagnosis. While the TCM medications reviewed here are typically used for common musculoskeletal ailments associated with pain, such as arthritis, it is important to seek a diagnostic evaluation by a clinician trained in TCM prior to reaching out for treatment.

Topical TCM treatment is widely utilized for muscle injuries within the Chinese community and comes in various forms, including paste, patch, balm, liniment or oil. Generally, side effects of these topicals are rare, although instances of contact allergy and dermatitis occasionally occur. However, many topical TCM products consist of multiple herbs, often ranging from 5 to over 20 herbs. This complex herbal mixing challenges our understanding of the individual components’ underlying therapeutic mechanisms. Only a few studies of TCM products have been able to provide evidence-based scientific data to support their efficacy.

Three popular and easily accessible herbs used topically for pain include:

(1) Carthami Flos (Carthamus tinctorius L.). A Chinese herb traditionally used for cardiovascular disease and bone injury in China to improve blood circulation. Limited studies support its benefit for vascular health.

(2) Dipsaci Radix (Dipsacus asperoides) A common herb used for musculoskeletal trauma. It promotes blood circulation to remove hematomas and alleviate pain. Recent scientific studies demonstated that Akebia Saponin D, the most abundant constituent of Dipsaci Radix, has anti-inflammatory effects.

(3) Rhei Rhizoma (Rheum palmatum Linn). A widely used traditional Chinese herb for wound healing. One of its derivatives, emodin, has been reported to promote the repair of excisional wounds in animal studies through complex mechanisms involving the stimulation of tissue regeneration .

CDR (Carthami Flos (Carthamus tinctorius L.), Dipsaci Radix (Dipsacus asperoides), Rhei Rhizoma (Rheum palmatum Linn)

A combination of the three herbs above as an herbal paste (named CDR) was found in clinical trials to be effective when applied topically for the treatment of conditions such as fifth metatarsal fractures and plantar fasciitis. A current study demonstrated that topical CDR treatment effectively enhances the regeneration, remodeling and maturation phases of muscle regeneration subsequent to injury.

DAEP – Dipsaci Radix, Achyranthis Bidentatae Radix, Eucommiae Cortex and Psoraleae Fructus

This herbal formula was simplified from a classic prescription “Xu Duan Wan” from “Fu Shou Jing Fang” has been used for treating the soreness and weakness of knees traditionally. These four herbs were selected for study in an animal model of knee arthritis based on their popularity in traditional practice. They include Dipsaci Radix (Dipsacus asperoides (DR), Achyranthis Bidentatae Radix (Achyranthis bidentata Blume) (ABR), Eucommiae Cortex (Eucommia ulmoides Oliv.) (EC) and Psoraleae Fructus (Psoralea corylifolia L.) (PF). An animal study evaluated the topical application of these four herbs as a paste named DAEP.

Effectiveness

Topical application of DAEP herbal paste to relieve knee pain due to osteoarthritis (OA) appears effective.

Mechanism of Action

Recognizing the underlying differences in TCM and western medicine, contemporary researchers still seek to determine a framework of how TCM medications work within a western model. In the case of DAEP, it is believed that its components are effective in arthritis pain because of its anti-inflammatory ingredients within the paste that target the suppression of the NF-κB pathway that promotes inflammation. Moreover, DAEP is thought to possibly suppress the progression of OA.

Constituent Ingredients Commonly Found In Chinese Herbal Medications (CHM)

Due to the large number of ingredients in Chinese herbal medication (CHM) formulations, the 3 most common are presented here.

Borneol

The most frequently included ingredient used in topical CHM formulations, borneol (bing pian), is non-toxic and non-irritating with a long history of use in CHM. Animal studies have shown it enhances permeation and drug delivery across skin, the blood-bran barrier and mucosal membranes.

Evidence for effectivness of borneol for pain includes a clinical study of 122 postoperative patients that found that when compared to placebo, a single topical application of 25% borneol for approximately 30 to 60minutes showed significantly greater reduction in postoperative pain without any adverse effects.

Xi Xin

The second most common ingredient is xi xin. Unfortunately no human studies of this ingredient alone appear to be available but animal studies support pain benefits for its extracts. The extracts include Methyl eugenol which is a major component of the essential oil of Asarum species, and Sarinin is a major lignin, a polyphenol known to have antioxidant, anti-inflammatory, and anti-cancer properties. Animal studies suggest methyl eugenol inhibits pain.

Xi Xin is derived from Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim) Kitag., Asarum sieboldii Miq. var. seoulense Nakai, and Asarum sieboldii Miq.

Yan Hu Suo

The third most common ingredient in the topical CHMs is yan hu suo, derived from the rhizomes of Corydalis yanhusuo. In human studies, levo-tetrahydropalmatine (l-THP), an alkaloids found in yan hu suo, is thought to be effective for pain and drug addiction with dose-dependent reductions in pain. Animal studies demonstrate pain benefis for 3 alkaloids derived from Corydalis: dehydrocorybulbine (DHCB), levo-corydalmine (l-CDL) and dehydrocorydaline (DHC).

Penetration Enhancers

Application techniques to enhance absorption

The frequency that one applies a topical medication can affect absorption. Though studies are sparse, multiple doses of topically applied drug have been shown to deliver more drug through the skin than single doses. For example, 1 gram of cream applied twice daily may deliver more drug than 2 grams of cream applied once daily.

Compounds to enhance absorption

To improve the absorption of medications into the skin and deeper structures, topical medications may include compounds to enhance the depth and speed of absorption of the medication. Examples of penetration enhancers include:

Menthol
Eucalyptus oil
Dimethylsulfoxide (DMSO)

Menthol

Menthols considered a rubefascient, a compound that simply turns the skin red, but functionally does so by increasing local blood circulation and vasodilation in areas in which it is applied. This process facilitates the absorption of medications into the skin and deeper structures which enhances their therapeutic benefits..

Eucalyptus Oil

Dimethyl sulfoxide (DMSO)

Dimethyl sulfoxide (DMSO) is a penetration enhancer used in compounded topical pain creams that has repeatedly occasioned concerns. DMSO appears to be used in compounded topical pain creams as both a penetration enhancer and as an active ingredient. While the evidence is far from conclusive, some studies suggest that DMSO may help treat osteoarthritis pain and complex regional pain syndrome . In fact, DMSO is the primary inactive ingredient in PENNSAID, an FDA-approved topical solution for osteoarthritis pain.

DMSO is a potent penetration enhancer but it may significantly enhance the absorption of other chemicals that could lead to their increased toxicity if applied at the same time. The instructions for use for PENNSAID caution patients to apply the medication to clean skin and to avoid the application of other drugs or cosmetics to the area due to the potential for an increased absorption that could potentially lead to toxicity.

Excipients or “inactive” ingredients

A wide range of bases, vehicles, and solvents are used to formulate topical pain creams, generally described as excipients, and these compounds can influence the attributes and characteristics of the topical (i.e., taste, smell, texture). Excipients are frequently called “inactive” ingredients but excipients can ultimately affect the final performance of the topical by affecting properties such as solubility, stability, release of the active ingredient, and skin penetration.

Safety Precautions

When using a topical analgesic:

always read the package information before opening and using the medicine
use the dose recommended on the packaging
only apply to healthy, unbroken skin
rub gently into the affected area
do not use a heat or ice pack on skin where you have recently applied a topical analgesic (unless your health professional has said it is OK).
Keep out of the reach of children and pets.
Store between 20 and 25 degrees C (68 and 77 degrees F).
Throw away any unused medication after the expiration date.

NOTE: These precautions are a summary and may not cover all possible information. If you have questions about your medicine, talk to your doctor, pharmacist, or health care provider.

Side Effects

All medicines, including those that are applied to the skin, have the potential to cause side effects. After topical analgesics are applied, most of the medicine is found in the skin and tissues where it was rubbed in. This can lead to skin irritation or redness, itching or rash.

A very small amount of active ingredient is also absorbed into the blood stream, so very rarely people may experience any of the following:

breathlessness
nausea
indigestion
abdominal pain
swelling
gastritis (inflammation of the stomach)
allergy — skin rash, itching, hives, swelling of the face, lips, tongue, or throat
Mild skin irritation, redness, or dryness
contact dermatitis (inflammation of the skin following contact with the medicine).

This list may not describe all possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Resources:

New Articles

New Articles – Synergy

References:

Topicals – Analgesic Overviews

Topicals – Arnica

Clinical Trials, Potential Mechanisms, and Adverse Effects of Arnica as an Adjunct Medication for Pain Management – 2021

Topicals – Formulations

Topical Analgesics – Critical Issues Related to Formulation and Concentration – 2016

Topical Cannabinoids

CBD – Quality Control

Topical CBD

Tolerability profile of topical cannabidiol and palmitoylethanolamide a compilation of single-centre randomized evaluator-blinded clinical and in vitro studies in normal skin – PubMed – 2021

Topical – Chinese (TCM)

Topical Clonidine

Topical Compounded Medications

Topical Essential Oils & Aromatherapy

Topical Frankincence (Boswellia Serrata)

Topical Gabapentin

Topical Ketamine

Topical Lidocaine

Topical Menthol

Topical NSAIDs

Topical NSAIDs – Bioavailability

Topical Opioids

Topical PEA

Topicals – Neuropathic Pain

Topicals – Arthritis

Topicals – Rheumatoid Arthritis

Topical Terpenes

Terpenes – Routes of Use:

Terpenes – CB2 Receptor

Topical Terpenes – Wound Healing:

Beta-caryophyllene enhances wound healing through multiple routes – 2019

Topical Terpenes – Individual Terpenes

Topical β-Caryophyllene

Synergies

National Academy of Sciences

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

Emphasis on Education

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

Should you wish more information regarding any of the subjects listed – or not listed – here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

For more information, please contact Accurate Clinic.

Supplements recommended by Dr. Ehlenberger may be purchased commercially online or at Accurate Clinic.

Please read about our statement regarding the sale of products recommended by Dr. Ehlenberger.

Topical Medications for Pain

Link to videos on this topic on Dr. Ehlenberger’s Youtube channel:

Links to other Pertinent Educational Pages:

See also:

Key to Links:

Links to topical medications by condition:

Links to individual topical medications:

Topically Applied Medications

Topically Applied vs Orally Ingested Medications

Where to Start?

Medical conditions that may respond to topical medications include:

1. Acute & Chronic Muscle Pain (sore muscles and trigger points), Sprains and Tendonitis

2. Arthritis (Degenerative or Osteoarthrits and Rheumatoid Arthritis)

3. Neuropathic Pain – Neuropathy, Fibromyalgia, Carpal Tunnel Syndrome

Recommended Topical Medications

Cannabidiol (CBD)

Beta-Caryophyllene (BCP)

Topical PEA (Palmitoylethanolamide) (OTC)

CBD/BCP (OTC from AliceCBD.com)

BCP/PEA (“Soothe”) – TullaBotanicals.com

Topical Lidocaine

Topical Diclofenac (OTC & Rx)

Capsaicin

Other OTC Topical Medications

Menthol & Camphor

Menthol and. Diclofenac

Natural, Plant-Based Compounds

Compounded Topical Medications

Non-Steroid Anti-inflammatory Drugs (NSAIDs)

Neuropathic Agents:

Antispasmodic Agents:

Traditional Chinese Topical Medications

Penetration Enhancers

Excipients or “inactive” ingredients

Safety Precautions

Resources:

References:

Topicals – Arnica

Topicals – Formulations

CBD – Quality Control

Topical CBD

Topical Terpenes

Terpenes – Routes of Use:

Terpenes – CB2 Receptor

Topical Terpenes – Wound Healing:

Topical Terpenes – Individual Terpenes

Topical β-Caryophyllene

Synergies

Emphasis on Education

For more information, please contact Accurate Clinic.

Accurate Supplement Prices