Prolotherapy:
A Literature Review and Retrospective Study
Robert G. Schwartz,
M.D. and Noreen Sagedy, M.D.
Department of
Physical Medicine and Rehabilitation, Medical University of S.C. , Charleston,
SC, USA and Medical University of SC, School of Medicine, Charleston, SC, USA
Abstract.
Proliferative therapy (prolotherapy) is
the process whereby dextrose, P25G or sodium morrhuate is injected into
ligaments in order to produce a proliferating response of that ligament. The
purpose of these injections is to strengthen ligamentous structures and
relieve pain. A review of the literature is provided and a retrospective study
presented which demonstrates a 66% reduction of sacroiliac low back pain in
two-thirds of the patients who received this form of treatment.
Ligaments consist of
many strands of fibrous tissue which may run parallel or crisscross at various
angles to each other. They provide stabilization of joints in all positions.
Pain occurs when normal tension on a ligament stretches the fibers. This
results in stimulation of the sensory fibers which do not stretch along with
the ligament 1. In sprain or tearing, the fibers become separated
from bone, and there is an accumulation of lymphy or blood at the site of
injury. Healing occurs through initiation of the wound response cascade
mediated by chemotactic agents and inflammatory cells. Fibrin is produced and
develops into a permanent strong fibrous tissue attached to bone. There is
also a production of bone at the enthesis 1. The healing process
can be interfered with. Subsequent activity can cause separation, or the
repair capacity in the individual can be deficient. This results in ligament
relaxation which is a weakness of the attachment. If this remains,
predisposition to repeat injury, chronic pain, and altered range of motion can
persist1,2.
The healing process
can be stimulated by the infiltration of a proliferative solution within the
ligament. Thus, the development of firm permanent fibrous tissue with
reduction of pain can take place1-8.
Literature
Review
The rich
supply of nerve endings in articular ligaments was first described by Lerich
in 1930 and later by Gardner in 1953. Hackett described most joint pain as
ligament pain. He was the first to scientifically demonstrate a method of
strengthening ligaments by the injection of a proliferative solution.
Inflammation was produced and a permanent increase in ligament size by 35-40%
resulted. Hackett claimed a cure rate of 82% in 1600 patients with low back
pain1. At this time, proliferative therapy was know as
sclerotherapy. This was because the irritants used in prolotherapy were thought
to work by creation of scar tissue rather than by the development of
proliferative response. Tome of the irritants used in prolotherapy had been
used to sclerose varicose veins as well5.
A 1982 study by Li
et al. quantified biochemically in a double-blind study the influence of
injecting a proliferative solution (100 ml of 5% sodium morrhuate) into rabbit
medical collateral ligaments in situ. Results revealed a highly signigificant
increase of the ligament's mass, thickness, enthesis strength, and its
weight/length ratio in comparison with the saline injected controls9.
A 1985 study, also
using 5% sodium morrhuate, was conducted by Maynard et al. They did a series
of five 100ml injections into intact rabbit patellar tendons and achilles
tendons. This study showed that not only is there an increase in the number of
cells but also a wider variety of cell types, including fibroblast,
neutrophils, lymphocytes, plasma cells, and unidentifiable cells in the
injected tissues. An increase in water content and amino sugar content were
also noted. Interestingly, a decrease in the mean collagen fibril diameter and
hydroxyproline content were documented despite an overall increase in fibrin
mass10.
In 1987, a double -
blind study was done by Ongley et al. comparing 40 patients who received
spinal manipulations and ligament strengthening proliferative therapy with 41
patients who received minor manipulations and 0.9% saline injections. One
injection per week was done for 6 weeks. The solution used was 2.5 % phenol /
25% dextrose / 25% glycerin / 47.5 % pyrogen free water (P25G). At 6 months
following the end of the treatments, 35 patients in the experimental group
reported greater than 50% improvement compared with only 16 in the control
group. Furthermore, 15 patients in the experimental group were disability-free
compared with 4 patients of the control group reporting no disability3.
In a different study
by R.G. Klein in 1989 histologic documentation of ligament proliferation in
human subjects in response to proliferative injections was demonstrated.
Biopsy specimens of posterior sacroiliac ligaments were performed pre- and
post treatment in three patients with low back pain. Each patient received a
series of six weekly injections using the P25G solution into the sacroiliac
ligaments. The proliferative injections resulted in collagen of objectively
increased diameter and was associated with decreased pain along with an
objective increase in range of motion4.
Biochemical
Basis
The healing of a wound has been divided into three phases: (1) inflammatory
(early and late), (2) granulation tissue formation, and (3) matrix formation
and remodeling11. Inflammation is the reaction of living tissues to
all forms of injury. It involves vascular, neurologic, humoral, and cellular
responses at the site of injury. Increased vascular permeability is the first
mechanism. It allows the escape of plasma proteins and white cells. This is
known as exudation. Neutrophils appear in perivascular spaces and they are
followed by monocytes/macrophages11.
The most important
chemotactic factors for both neutrophils and macrophages include C5a, a
component of the complement system, leukotriene B4, a product of a rachidonic
acid metabolism, and bacterial products. Macrophages are also attracted by the
basic peptides in the lysosomal granules of neutrophils and this explains why
they appear as the second line of defense. These cells then destroy or
neutralize the injurious agent by phagocytosis allowing for the repair of the
damaged site to then occur12.
Repair is the
process by which lost or destroyed cells are replaced by new, living cells.
The tissue defect is initially filled up with highly vascularized connective
tissue called granulation tissue. It consists of newly formed small blood
cells embedded in loose ground substance containing fibroblasts and
inflammatory cells. Fibroblasts migrate into the wound bed under the influence
of chemotactic factor11,12.
As granulation
tissue matures, inflammatory cells decrease in number, fibroblasts lay down
collagen, and the capillaries become less prominent. An a vascular, relatively
a cellular tissue with inactive spindle-shaped fibroblasts tucked in between
collagen fibers emerges. The collagen fibers then aggregate into mature
fibrils. The acquisition of tensile strength follows a sigmoid curve12.
The orderly movement and proliferation of cells within a healing wound is
influenced by both cell signals and extra cellular matrix (e.g., fibronectin
and growth-stimulating factors). Thus, a wound-healing cascade is present. The
growth associated with repair is regulated and ceases when healing is
completed12.
Proliferants are
substances which cause a localized tissue reaction leading to an inflammatory
response. The wound - healing cascade is thus triggered resulting in
fibroplasia and collagen deposition. The healing cascade begins with
granulocyte infiltration followed by monocyte/macrophage invasion. Growth
factors are released and thus activated fibroblasts are recruited to the site
to secrete new matrix. This new matrix includes collagen fibrils2,6,7,13.
Any factor which leads to fibroplasia can be a proliferative. There are three
categories of proliferants that have been used: irritants, osmotic shock
agents, and chemotactic agents Irritants (e.g., phenol, quaicol, tannic acid,
and quinine) create a local tissue reaction which causes granulocyte
infiltration. Osmotic shock agents (e.g., glucose, glycerin, ZnSO4) create a
local tissue reaction to stimulate a granulocyte infiltration by dehydration.
Dhemotactic agents (e.g., sodium morrhuate) cause direct activation of local
inflammatory cells13.
In some instances
the injected factor is altered in vivo. Phenol oxidizes to reactive quinine
and sodium morrhuate as an arachidonic acid compound is a precursor to many
cytokines, including leukotrienes, thromboxanes, and prostaglandins13.
Growth factors are a fourth category currently being researched at Biogenteic
Laboratories (e.g., EFG, PDGF, IFG-I, FGF, TGF-beta). They directly recruit
and activate local fibroblasts13.
Materials
And Methods
The effects of prolotherapy on 43 patients with chronic sacroiliac strain were
retrospectively reviewed. There were no sciatic tension signs, motor weakness,
sensory deficits, or patients with bone abnormalities entered into the study.
The patients had all failed to respond to other forms of treatment including
surgery. Ages ranged from 20 to 70 years.
Treatment consisted
of three injections into the insertion of the posterior sacroiliac ligament,
beginning at its most caudal one-third and moving superiorly by one-third of
its length with each injection (fig. 1)
 Figure1 |
Fig.
1. Needle Location used for injection of the sacroiliac ligaments.
Trigger
point of ligaments: (IL) Iliolumbar: (LS) Lumbosacral-supra and
interspinus: (A,B,C,D,) Posterior sacroiliac; (SS) Sacroapinus; (ST)
Sacrotuberus;(SC) Sacrococcygeal;(H) Hip-Articular; (SN) Sciatic
nerve (With permission from G.S. Hackett, Ligament and Tendon
Relaxation. Charles C. Thomas Co. , 1958)
|
The injections were
done 2 weeks apart. The proliferant used was a mixture of 1 cc of 5% sodium
morrhuate and 1 cc of 1% Xylocaine. A needle of proper length was used that
assured the proliferant was placed on bone. The solution was distributed
throughout the fibro-osseous junction.
Each patient was
informed that there would be a 2- to 3- day period of discomfort in the area
of the injection due to the initiation of the wound-healing cascade.
Instructions were given to avoid aspirin, ibuprofen, or other
prostaglandin inhibitors, and to use only acetaminophen to relieve pain.
Activity was encouraged. The patients were instructed in sacroiliac
mobilization exercises and fitted with a sacroiliac belt.
Each patient was
seen on 2-week follow-up after the third injection. Subjective percentages of
relief were recorded. If satisfactory pain relief had been obtained, they were
discharged from treatment and instructed to return on an as-needed
Results
At the conclusion of
the three injection series, on 2-week follow-up, 20/43 patients reported 95%
improvement, 31/43 75% or better improvement, and 35/43 reported 66% or
better improvement. Thus, 2/3 of the patients received 66% relief. No
improvement was reported by 3/43. While no formal mechanism for prolonged
follow-up was in place 10/40 or 25% reported some level of recurrence (Table
1).
Table 1
| Relief
obtained in 43 patients after a series of prolotherapy injections
(three injections, once every other week) |
| No.
Of patients |
0%
|
33%
|
50%
|
66%
|
75%
|
99% |
| (43
total) |
Relief |
Relief |
Relief |
Relief |
Relief |
Relief |
| Reported Relief |
3 |
1 |
4 |
4 |
11 |
20 |
| Recurrence |
|
1 |
1 |
2 |
2 |
4 |
Discussion
The sacroiliac joint
can be considered to be unstable when the ligaments are relaxed. Because of
this joint's weight-bearing spinal mechanics the ligaments supporting it
frequently become damaged. This can lead to intense pain, which may become
chronic. It can result in abnormal compensatory movement as well. The altered
spinal kinesiology can lead to further injury of other structures such as
lumbar vertbrae, sacrum, and intervertebral disks.
Prolotherapy is
designed to strengthen the sacroiliac ligaments so as to develop normal
tension in them. Numbing of the ligament with Xylocaine and obtaining
immediate relief provides for temporary comfort from the injection. The
ensuing painful reaction that occurs from the proliferative injection
represents the activity of the initiated wound-healing response. Prostaglandin
inhibiting medications should be avoided.
It important to
choose the proliferative solution wisely and to make sure the needle is on
bone when injecting. Three cases of paralysis and two deaths have been
documented after in advertant injection of psyllium seed oil and zinc sulfate
into the subarachnoid space14-16.
Other investigators
have used a phenol/dextrose/glycerin solution (P25G) and obtained significant
results without complications. While the percentage of phenol in P25G is very
dilute and probable safe, many clinicians prefer to use either dextrose or
sodium morrhuate, as both of these agents have also been used intravenously
for other medical conditions8,17.
Prolotherapy has
been utilized at other ligamentous structures in addition to the sacroiliac
area. Intraspinous, ileolumbar, fibulocalcaneal, medial and lateral collateral
(about the knee), radiohumeral, coracoclavicular, and sternoclavicular
ligaments are frequent ligamentous injection sites. Intraarticular ligamentous
injections have also been performed2,7,8.
Although this study
is a retrospective one, the data support the studies of Lui, Maynard, Ongley,
and Klein. While we have not done biopsy studies to prove a proliferative
effect occurred, we did obtain significant pain relief without any undue side
effects2,3,9,10.
Conclusion
We conclude from this study and the aforementioned literature that it is
possible to induce proliferation of collagen in human ligaments using
prolotherapy. The tissue that proliferates is a dense collagen and is
associated with a reduction in pain. Mechanical back pain can be relieved by
this method and other compensatory injuries prevented.
References
1.
Hackett GS. Ligament and tendon relaxation treated by prolotherapy, 3rd ed.
Springfield, Ill: Charles C. Thomas, 1958
2.
Cyriax J. Textbook of orthopaedic medicine. Philadelphia: Bailliere
Tindall, 1982
3.
Onlgey MJ, Klein RG, Dorman TA, Eek BC, Hubert LJ. A New approach to the
treatment of chronic low back pain. Lancet 1989; 11:143-146
4.
Klein RG, Dorman TA Johnson CE. Proliferant injections for low back pain:
histological changes of injected ligaments and objective measurements of
lumbar spine mobility before and after reatment. J Neurol Orthop Med Surg
1989; 10:123-126
5.
Injection therapy helps low back pain, study reveals. Back Pain Monitor
1988; 6:12:161-172
6.
Gearhardt JJ. Interdisciplnary rehabilitation in trauma. Baltimore, Md:
Williams and Wilkins, 1987
7.
Mirman MJ. Sclerotherapy. Springfield, PA, 1986
8.
Leedy RF. Basic techniques of sclerotherapy. Osteop Med 1987;9
9.
Liu YK, Tipton CM, Matthes RD, Bedford TG, Maynard JA, Walmer WC. An in
situ study of the influence of a sclerosing solution in rabbit medial
collateral ligaments and its junction strength. Connect Tissue Res 1983;
11:95-102
10.
Maynard JA, Pedrini VA, Pedrini-Mille A, Romanus B, Ohlerking F.
Morphological and biochemical effects of sodium morrhuate on
tendons. J Orthop Res 1985;3:236-248
11.
Wyngarden JB. Cecil textbook of medicine. Philadelphia;W.B. Saunders, 1988
12.
Robbins SL, Kumar V. Basic pathology, 4th ed. Philadelphia: W.B. Saunders,
1987
13.
Banks A. Biochemical effects of prolotherapy. First Annual High Country
Prolotherapy Workshop, Denver, Co., 1989
14.
Hunt WE, Baird WC. Complications following injections of sclerosing agent
to precipate fibro-osseouis proliferation. J Neurosurg 1961; 18:461-65
15.
Keplinger JE, Bucy PC. Paraplegia from treatment with sclerosing
agents-report a case. JAMA 1960: 73:1333-36.
16.Schneider
RC, Williams JI, Liss L. Fatality after injection of sclerosing agent to
precipitate fibro-osseous proliferation. JAMA 1960; 170:1768-1772
17.
Lawson AW. Acute esophageal variceal sclerotherapy. JAMA 1986; 255:497-500