Prolotherapy for chronic back pain

Internal Medicine News, Nov 1, 2007 by Nancy Walsh

History and Rationale for Use

Prolotherapy, or proliferative injection therapy, involves the injection of irritant substances into regions of ligaments and tendons with the intention of strengthening the ligaments through local proliferation of granulocytes, fibroblasts, macrophages, and growth factors.

Similar techniques were used in the late 19th century for hernia repair and in the 1930s for subluxation of the temporomandibular joint. Prolotherapy gained popularity after Dr. George S. Hackett gave a presentation on it at the 1955 annual meeting of the American Medical Association.

A variety of substances from three classes of proliferants have been used with this technique; osmotic proliferants are the most common. This class includes solutions of glucose, glycerin, and zinc sulfate that act by provoking cellular osmotic shock, which causes the release of proinflammatory cytokines. A second category, referred to as irritants, can damage cell surfaces, rendering them antigenic. This category includes phenol, tannic acid, and guaiacol. The third type, chemotactics, also cause a local influx of inflammatory cells. Sodium morrhuate belongs to this class.

Clinical Studies

A recent Cochrane review identified five high-quality studies that included 366 patients aged 18 years and older with chronic low back pain. The protocols in these studies were notably heterogeneous, which the authors acknowledged made intertrial comparisons difficult and meta-analysis and levels of evidence summaries impossible (Cochrane Database Syst. Rev. 2007 [Epub doi: 10.1002/14651858.CD004059.pub3]).

One study compared injections of a solution containing glucose, glycerin, phenol, and lidocaine with injections of a control solution of normal saline, whereas two studies compared a glucose, glycerin, phenol, and lidocaine solution with a lidocaine control solution. A fourth compared a glucose plus lidocaine solution with saline solution, and the fifth compared a solution of phenol, dextrose, glycerin, and procaine with a procaine control solution.

The authors of the review reported that three studies comparing prolotherapy alone with control injections alone found no evidence for efficacy, while benefits were seen in the two studies that compared prolotherapy plus other modalities such as spinal manipulation and exercise.

Of the two positive studies, one that included 79 patients found that a greater proportion of patients in the active prolotherapy group had achieved a decrease of 50% or more in pain or disability at 6 months after a series of six weekly injections, compared with patients in the control group, who received injections of xylocaine/saline solution (J. Spinal Disord. 1993;6:23-33).

Another study that included 81 patients found that a regimen of spinal manipulation plus proliferant injections of a dextrose, glycerin, and phenol solution was more effective in reducing pain than was a program of sham manipulation plus saline injections. Significant differences favoring the prolotherapy treatment also were seen between the groups in the proportion of patients who had an improvement in disability scores of more than 50% at 6 months. This proportion was 88% in the group who received prolotherapy, manipulation, and exercise, compared with 39% in the control group (Lancet 1987;2:143-6).

This last study "has some of the most impressive results for low back pain I've ever seen as a researcher," the lead author of the Cochrane review, Simon Dagenais, D.C., Ph.D., said in an interview. He and his colleagues concluded that "prolotherapy injections alone do not have evidence of a role in the treatment of chronic low back pain. However, repeated ligament injections ... may give prolonged partial relief of pain and disability as part of a multimodal treatment program when combined with spinal manipulation and exercise."

Dr. Dagenais and his colleagues have sought permission from the Food and Drug Administration to proceed with further studies, but the agency has been reluctant to accept the older data. He has therefore completed two animal toxicity studies, and once the data analysis is complete, he plans to file an investigational new drug application for a phase I study of the dextrose, glycerin, phenol, and lidocaine mixture.

"If all goes well, we will proceed to phase II and eventually phase III, where we will do a properly designed, randomized, controlled clinical trial with a large number of patients and hopefully answer the questions that remain about prolotherapy for chronic low back pain," said Dr. Dagenais, of the division of orthopedic surgery, University of Ottawa, and the CAM Research Institute, a nonprofit organization based in Irvine, Calif., that is sponsoring this research.

Safety Concerns

With the burgeoning of prolotherapy in the 1950s came clinical experimentation with a variety of irritant solutions, sometimes by inexperienced practitioners, and several serious adverse events occurred. One 50-year-old woman who received injections of a solution of zinc sulfate and phenol solution developed adhesive arachnoiditis and hematoma and subsequently died. A second patient, a 53-year-old woman, was injected with vegetable oil and anesthetic and developed spastic paraplegia that was unrelieved by laminectomy.