Subcutaneous Perineural Injections

Perineural Subcutaneous Injections (PSI)

Definition: Injection close to subcutaneous (“under the skin”) nerves to restore their normal function.

How PSI Works: There is another type of inflammation that has been recognized, called neuropathic inflammation. This type of inflammation is produced by special small sensory nerves that are protein producing (“peptidergic”). These nerves normally produce proteins that can be healing or damaging. When produced damaging proteins that is called “neuropathic inflammation” (see below). There are many scientific articles published each month on this type of inflammation. Dextrose injection in low concentration (5%) reduces neuropathic inflammation. This does not stimulate AA inflammation; the primary intent is to treat nerves, not ligaments, tendons, or cartilage. The primary intent is not to grow new tissue. That is why, although related, we no longer describe this as “prolotherapy.”

Why can’t you take a pill for reversing nerve inflammation? There are a number of medications that calm the nerve, but don’t heal it; some of these meds are gabapentin (Neurontin), pregabalin (Lyrica) or duloxetine (Cymbalta).  However, medications that reduce the actual nerve inflammation of nerves all over the body, also create undesirable side effects such as:

  • dizziness
  • drowsiness
  • weakness
  • constipation
  • blurred vision,
  • loss of balance or coordination.

These side effects have blocked the completion of some clinical trials, although medication trials continue.  Injection to directly treat the nerves does not affect nerves all over the body, so side effects are not seen. In addition, there are creams which help reduce nerve inflammation, with mannitol cream particularly well tolerated.  Vitamin D cream helps as well but is made by compounding pharmacies and will be more expensive.   Dextrose cream helps but is “tacky” on the skin.  



 “Bad Nerves”, Nerve-Based Inflammation, and Why Arthritis Meds Don’t Help

The “Dr. Jekyll and Mr. Hyde” of chronic pain - TRPV-1 Nerves

In the story of Dr. Jekyll and Mr. Hyde, Dr. Jekyll drinks a potion that causes him to switch back and forth between a very good Dr. Jekyll and a very evil Mr. Hyde. In 1997, a very important protein was completely identified to the point it was successfully reproduced (cloned). This protein sits on the surface of some protein-producing (peptidergic) nerve cells. That protein is called a receptor, because it receives information that causes it to change what the nerve cell does. If the receptor is “mellow” (down-regulated), the nerve cell will be very “good” (produce healthy, non-pain producing proteins). If the receptor is “over-active” (up-regulated), then the nerve cell will be very “evil/bad” (produce damaging and pain-producing proteins). Thus, this small protein receptor on the surface of the nerve cell is the “potion” that will make the nerve cell quickly (in seconds) change its character from “very good” to “very bad.” This receptor is called TRPV-1 (transient receptor potential vanilloid - Type 1). We will call the sensory nerves that are controlled by this receptor “TRPV-1 nerves.” The whole “system” of sensory nerves occurs throughout the body, supplying virtually all areas, and is termed the “peptidergic sensory system” because of the ability of these nerves to make proteins (peptides) to affect other structures. For simplicity, we will focus on the nerves that supply the skin that are now thought to be involved the most in chronic pain. We will call these nerves simply TRPV-1 nerves or “T-nerves.”


What Happens When TRPV-1 Nerves Behave Badly – Neuropathic Inflammation

When the TRPV-1 receptor is “over-active” (up-regulated), the TRPV-1 nerve produces proteins that directly cause pain (Substance P is an important one) and proteins that can cause breakdown in all soft tissue structures (CGRP-1 or calcitonin-gene-related peptide is an important one). When the TRPV-1 nerves are producing degenerative proteins that damage other structures, it is called Neuropathic (nerve-caused) Inflammation.


Why Anti-Inflammatory Medications Don’t Work For Neuropathic Inflammation

Anti-inflammatory medications target the AA-inflammation and often do so by blocking cyclooxygenase. Blocking cyclooxygenase does not affect the N inflammation pathways. Anti-inflammatory medications have some pain-relieving ability other than just by blocking AA inflammation, so they can be useful, although seldom strikingly useful.


How Do Bad Nerves Affect Other Structures

(ie, ligaments, tendons, and cartilage) And Cause Chronic Pain?


Hilton’s Law: TRPV1 nerves connect to all other structures and interconnect with each other.

Hilton’s Law indicates that nerves that cover the skin are joined by nerves from joints, ligaments, and tendons on their way to the spinal cord.


Switching Road Signs”  :   How to transport good or bad proteins to ligaments, tendons, joints, nerves

In many spy novels, a trick often used is to switch directional arrow signs to point in the incorrect direction. Sensory nerves (including TRPV-1 nerves) are equally good at conducting (and transporting proteins) both forward and backward along nerves. On the way to the spinal cord there are many branches that come together, not only from the skin, but from other structures. These proteins can easily “have the road sign switched” and transport their proteins backwards along nerve paths and into other structures. Thus, any irritative protein produced by TRPV-1 nerves can have a wide influence on structures in the area.


How to Make A TRPV-1 Nerve Behave Badly, and

Why Nerves Under the Skin Are Commonly Affected



An important quality of TRPV-1 sensory nerves

Animal studies have clearly demonstrated that simply surrounding a nerve around its entire circumference, even without squeezing it, will shut off fast conduction in that nerve, and cause it to behave abnormally. This depiction illustrates how merely touching a nerve on all sides will lead to a swelling reaction. Although the nerve was merely touched, the area can become a point of constriction as the nerve swells on either side of the constriction. Those patients that have heard of Morton’s Neuroma in feet may be interested that this is how nerves in the feet swell up and become neuromas.


"Skin Nerves" in humans are very easy to damage and become pain sources…

These figures show how sensory nerves travel along the skin and then suddenly dive through a layer of fascia to make their way between muscles to travel deeper toward the spinal cord. The first figure shows the collarbone (clavicle) and neck of a person from the front and a very important nerve that has three parts that dive through fascia above the collarbone. The second figure shows openings in the fascia to allow the nerve to make its way through more easily. These nerves or the fascia are very easy to damage since they are right on the surface. If the fascia does not work right it can “button hole” the nerve, as seen in the last figure. Because these nerves are so “claustrophobic,” they begin acting abnormally quickly.


Skin Nerves Are Easy to Keep Irritated By Muscle Contraction, Being Hit, or by Holding Positions (ie, bad posture)

Because muscles are contracting frequently, and because skin nerves are flat and often change direction suddenly to dive between muscle layers, the TRPV-1 nerves from the skin are easily irritated. Also, they are so easy to hit. For example, notice on this picture the location of nerves on the front of the knee. Hitting the knee cap or on the side of the knee cap could irritate these nerves and make them swell, and thus have more difficulty fitting through the hole in the fascia.



Three studies have now been published, all consecutive patient type...

1)  Lyftogt J. Prolotherapy for recalcitrant lumbago. Australas Musculoskeletal Med 2008;13(5):18-20.

46 consecutive patients with low back pain (without leg pain) were seen. 2 were diagnosed with hip pain and sent for surgery. 2 dropped out before treatment. 1 was treated twice and dropped out in favor of a non injection treatment..Of the remaining 41 patients 24 (58%) were male and 17 (42%) female. Mean age was 48.3 (range 23-73) years. Mean duration of symptoms was 5.5 years (range 1- 264 months). The swollen and tender nerves were clinically identified and treated with "percutaneous near nerve injections" approximately 1 ml every 2 cm. The objective of the treatment was to achieve a complete local anesthetic response for all low back pain at the time of the treatment. The solution used in the earlier part of the audit was hypertonic dextrose 20-40%, mixed with 0.1% lignocaine and/or ropivacaine 0.1% in normal saline. Towards the end of the treatment the solution consisted of dextrose 20%, lignocaine 0.1% and cholecalciferol (Vit D) 1000 IU/ml in normal saline. In the earlier phase of the audit period "tender points" were targeted mainly along the latissimus dorsi tendons, the gluteus maximus origin and the supraspinous ligament. In the latter phase the focus became the "inflamed" superior and intermediate cluneal nerves and thoracic spinal nerves where clinically indicated. Mean initial VAS was 7.6 (range 5-10). Mean VAS at last treatment was 1.4 (range 0-6). Mean duration of treatment was 8.3 weeks (range 1-17). The mean number of treatments was 6.2 (range 2-16). Ninety percent of patients improved more than 50%, and 10% less than 50%. Twenty-nine percent of patients reported no pain at the last consultation. Long term followup results were not stated.


2)  Lyftogt J. Subcutaneous prolotherapy for Achilles tendinopathy Australas Musculoskeletal Med Nov 2007;12(11):107-109.

Different dextrose concentrations were clinically trialed over a four-year period with long-term follow up of 132 Achilles tendons. Results are broken down by year and cannot be looked at in total with information given. A representative year was 2006 in which 30% glucose was use in 0.1% ropivacaine and 0.1% lidocoane. In that year 34 tendons in 31 subjects were treated with mean age 47 (28-69) years, and mean symptom duration of 14 months (1-60). The mean length of treatment was 7.6 weeks (3-15 weeks) 84% were available for long term followup at mean of 12 months with mean VAS change from 6.7 to 1.1 and 88% of those that were contactable at 12 months satisfied with treatment.


3)  Lyftogt J. Subcutaneous prolotherapy treatment of refractory knee, shoulder and lateral elbow pain. Australas Musculoskeletal Med 2007;12(2):110-112.

In 2005, 127 painful knees (74), shoulders (33) and lateral elbows (20) were treated with subcutaneous prolotherapy. . The treatment was well tolerated and safe. The treatment protocol consisted of weekly treatments where possible. All active TPs were identified by palpation and injected subcutaneously with 0.5-1 ml of a Glucose 20%/Lignocaine 0.1% solution. The objective at the time of each treatment was to achieve complete local anesthetic pain relief. Treatments were continued until VAS 0-1 and/or after consultation with the patient. The combined outcome statistics for the treatment of the 2005 knee, shoulder and lateral elbow pain showed a mean length of symptoms of 23.9 months and a mean treatment length of 7 weeks. The mean initial VAS 6.7 reduced at follow up of mean 21.4 months to VAS 0.76. The combined satisfaction rate at follow up was 91.7%. However, the follow-up success was an average of about 75% so approximately 25% were lost to long term followup.


K. Dean Reeves, M.D. is a physician and medical researcher in the area of pain caused by arthritis, chronic sprains and chronic strains. His private practice is located in the greater Kansas City area of Roeland Park, Kansas.  He collaborates in research with other locations across the country and internationally, and is licensed in the states of Kansas and Missouri.

Professional Bio & Publications             Contact

Copyright 2011-2014
Dr. K. Dean Reeves

No part of this site should be understood to be personal medical advice or instruction in how to perform injection therapy. A decision on treatment requires a good history and full examination and a knowledge of your treatment goals. Treatment decisions should be made in consultation with your personal healthcare professional and/or prolotherapist.