Intra-articular and Allied Injections Sureshwar Pandey, Anil Kumar Pandey
INDEX
×
Chapter Notes

Save Clear


Principles of Intra-articular and Allied InjectionsCHAPTER 1

 
INTRODUCTION
It is more than five decades from now that Philip Hench and his colleagues introduced the corticosteroids with a lot of fan and fair (triumphal and trumpeted introduction indeed) for managing rheumatoid arthritis at the Mayo clinic in 1949.
In fact Kendall and Hench in America and Reichstein in Switzerland jointly won the Nobel Prize for the introduction of cortisone, which was used for the first time in 1948 for treating rheumatoid arthritis. Soon after it was observed by Philip Hench and his colleagues at Mayo clinic (1949) that hydrocortisone was active at tissue level in reducing the inflammatory changes. However now responsible physicians always want to ward off the steroids or wean them off (if it has already being used) as far as possible. Of course, its one use still remains and perhaps will remain (till some harmless substitute come in the medical arena) universally employed and that is its intra-articular, periarticular and intra-lesional injections/infiltrations.
Joe Hollander (1951) was the first to introduce its local infiltrative use to control pain and limit the inflammatory process, whether induced by trauma, collagen arthropathy or crystallopathy or similar conditions. Oral use of corticosteroids is very popular with the physicians even general practitioners, but its local use demands a skilled approach, a knowledge placement and careful precautions to avoid infections. The surgeons or rheumatologists or gynaecologists or dermatologists or ophthalmologists need to know absolutely where, when, how, why and why not to use it.
Hollander was perhaps one of the first to use compound F (hydrocortisone acetate) into an inflamed joint due to rheumatoid arthritis, and had also used prednisolone tertiary butyl acetate to prolong the benefit. Hydrocortisone acetate (an acetate ester of hydrocortisone) is a very fine white odourless crystalline powder and is practically insoluble in water (considerably less soluble than the 2hydrocortisone in aqueous media). It melts at a temperature of 216–220°C. One gram dissolves in 230 ml of alcohol and 150 ml of chloroform.
The preparation most commonly effectively and widely used till recently is hydrocortisone tertiary acetate ester of triamcinolone acetinide (TATBA). The chemical formula of hydrocortisone acetate is C23H32O6. The injection available is a sterile suspension of hydrocortisone acetate in sodium chloride solution, containing a dispersing agent.
The usual dose of hydrocortisone acetate for intra-articular injection is 25 mg for an average joint with a variation from 0.5 to 50 mg. Several joints can be injected simultaneously.
 
MODE OF ACTION
Glucocorticoids diffuse across the cell membrane and form a complex with specific cytoplasmic receptors. These complexes enter the nucleus of the cell, bind to the DNA and stimulate transcription of mRNA, and later protein synthesis of various enzymes. On the whole, this is the basic biochemical action of the steroid which accounts for the various and numerous effects after the systemic use.
As such the mode of action of adrenocortical steroids has been mainly discussed around:
  1. Immune responses
  2. Anti-inflammatory properties
However they also influence the carbohydrate, protein and fat metabolism. They also affect the working of cardiovascular system, skeletal system, skeletal muscles and the central nervous system.
 
IMMUNE RESPONSES
The mode of immune responses, as yet, has not been clearly defined. They are believed to modify the clinical course of different diseases in which hypersensitivity is believed to play an important role. They do not interfere with the normal mechanism of development of cell-mediated immunity. Probably, they prevent or suppress the inflammatory responses that take place as a consequence of hypersensitivity reactions.
 
ANTI-INFLAMMATORY PROPERTIES
Researches are still on to understand clearly the anti-inflammatory properties of corticoids. However for the clinicians it is perhaps enough to understand that corticoids inhibit the inflammatory responses, whether the inciting agent is radiant, mechanical, chemical, infectious or immunological. It must be borne in mind that there is only suppression of the inflammatory effect, while the underlying causes of the diseases remain unaffected. It is this property of corticoids that provides them almost unique 3potential for therapeutic disaster. Hence, the epitomized remark, at times, stands true that corticoids, if misused, permit a patient to walk slowly all the way to the autopsy room. However, the recent works in more detail have projected variable positive thinking about the role of intra-articular corticosteroids.
Corticosteroids exert their anti-inflammatory action by interrupting the inflammatory and immune cascade at several levels including: impairment of antigen opsonisation, interference with inflammatory cell adhesion and migration through vascular endothelium, interruption of cell-cell communication by alteration of release or antagonism of cytokines (interleukin −1), impairment of leukotriene and prostaglandin synthesis, inhibition of production of neutrophil superoxide, metalloprotease and metalloprotease activator (plasminogen activator), and decreased immunoglobulin synthesis (Gaffney et al 1995).
Against earlier reported that corticosteroids injections may suppress cartilage proteoglycan synthesis, worsen cartilage lesion, or even cause degenerative lesion in normal cartilage (Raynauld 1999), recent reports have shown that low dose intra-articular corticosteroids (sufficient to suppress catabolism) normalised proteoglycan synthesis and significantly reduced the incidence and severity of cartilage erosions and osteophyte formation (Raynauld JP et al, 2003). In humans, repeated corticosteroid injection in knees of patients with chronic arthritis presented no evidence of destruction or accelerated deterioration (Friedman and Moore 1980).
The local or intra-articular injection of the corticoids does not appear to have significant systemic effects. However, it does not mean that it is all full proof. Slowly there may be a gross damage of the articular cartilage following injudiceous repeated use of intra-articular corticoids.
The local mode of action is again not clearly defined. Though pioneers have devoted their time and mind to illustrate the exact mode of action of intra-articular hydrocortisone acetate and allied substance (Table 1 on page 81) the controversy still exists. Kantrowitz et al (1975) suggested that the anti-inflammatory property of corticosteroid emanate from their capacity to inhibit production of prostaglandin (a potent mediator of inflammatory response) in the synovium.
Clinical effects of suppression of non-specific inflammation and reduction of swelling and pain to varying extent have been noticed in most of the cases with intra-articular injection of the corticosteroids. However, in certain cases it appears as only a pallative therapy and at another few occasions it proves to be ineffective.
It has been noticed that at times even a placebo injection into the joint or even just pricking into the joint helps in relieving the chronic pain to varying extent. This may be explained, more or less on the comparable lines of using electrical stimulation and acupuncture to relieve the chronic pain. 4Probably, they act by closing a hypothetical GATE in the spinal cord, thereby blocking pain stimuli from reaching the brain. Puncturing stimulates small nerve fibres sending impulses through the OPEN GATE that registers in brain as acute pain. When the signals reach the central biasing mechanism of the brainstem, they trigger counter impulses, which travel down the spinal cord and close the GATE against the chronic pain. However, this is just a hypothesis. Various research works, being done to find the effective ways and means of tackling the problem of pain, point to a new attractive approach basing upon the opposite principles of stimulating the inhibitory systems. Of course it is too early to provide an objective evaluation of such possibilities. Low doses of intra-articular steroids have been noticed to reduce the size, severity and progression of both, lesions of the cartilage and osteophyte formation (William 1985, Pelletier et al 1994).
Though Moskowitz et al (1985) and Behrens (1975) have raised the possibilities of adverse effects of intra-articular corticosteroids on the articular cartilage, varying benefits from such injections cannot be denied (Freidman 1980, Dieppe et al 1980, Pandey 1982), rather its judicious use can always be beneficial (Pandey 1982).
It has been general tendency to use intra-articular steroids in late stage of osteoarthritis or other similar arthritic conditions, but this strategy needs to be changed in light of the experimental evidences, which indicate that intra-articular steroids exert a chondro-protective effect—it is probably by the suppression of stromelysin synthesis, a metalloprotease implicated in osteoarthritic cartilage degradation. However, though pain relief by intra-articular corticosteroids can be dramatic, its long-term chondroprotective effects need further authentication.
Hydrocortisone the natural hormone, being too much soluble was found to disperse too quickly and thus could not leave its prolonged effects locally. Hence, its chemically improved ester form hydrocortisone acetate (C23H32O6) the primary alcohol group of C23 being the one esterified was developed and found to be suitable. It is considerably less soluble than hydrocortisone in aqueous media, rather for all practical purposes hydrocortisone acetate may be taken as insoluble in water. It melts at a temperature of 216–220°C. One gram dissolves in 230 ml of alcohol and 150 ml of chloroform. When prepared in microcrystalline form and mixed with other agents it forms a stable suspension, which can be injected locally where it remains deposited for several weeks, gradually releasing the hydrocortisone to produce its anti-inflammatory effects for longer period. The successful attempt to restore the comfort and mobility of rheumatoid affected joints by local injection of hydrocortisone acetate (compound F) into the inflamed joint was by Hollander, the Philadelphia rheumatologist in 1951. He used prednisolone tertiary butyl acetate to prolong the benefit. Mc Carty, the Hollander's colleague rheumatologist in Philadelphia, showed that the very long lasting synthetic 5corticosteroid derivatives, especially triamcinolone hexacetonide (TATBA or THA), could produce remarkable and lasting remissions of the rheumatoid arthritis effects when given as multiple injections at certain intervals, especially in smaller joints (e.g in hands). He equated the result to the ‘medical synovectomy’. With the pioneering work of these two rheumatologists ushered the art and science of local injection therapy for the rheumatic disorders. Of course, the experiences of ameliorating pain by injecting local anaesthetic agents into and around the painful spots in the muscles and painful ligaments in the sprains have definite role in establishing the local injection therapy for rheumatoid disorders and allied conditions.
Gradually, there has been great swing in favour of injecting methylprednisolone acetate (chemical name being 6-methyl-delta-1-hydrocortisone) in place of hydrocortisone acetate, wherever it is indicated. It is 6-methyl derivative of prednisolone. Methylprednisolone acetate posses the general properties of the glucocorticoid methylprednisolone, but is less soluble and therefore less readily metabolized. Thus, after injection into various sites its action is prolonged. It is more or less white odourless crystalline powder which melts at about 215 degree C. with slight decomposition and is practically insoluble in water. Its molecular formula is “C22H30O5” and has the molecular weight of 374.46.
Like other glucocorticoids, methylprednisolone causes profound and varied metabolic effects. These compounds have also been seen to modify the body's immune response to diverse stimuli.
 
POTENCY
The potency of 4 mg of methylprednisolone can be obtained from 4.4 mg of methylprednisolone acetate. The anti-inflammatory effect of 20 mg of hydrocortisone is available from the 4.4 mg of methylprednisolone acetate. Mineralocorticoid activity of methylprednisolone is minimal. 200 mg of methylprednisolone is equivalent to 1 mg of desoxycorticosterone. Intra-articular injection of Dysprosium-165-ferric hydroxide macroaggregates has been used for medical synovectomy, and has been proved to be an effective treatment for chronic rheumatoid synovitis of the knee with minimum radiographic evidence of lesion of bone and cartilage (stage I or stage II radiographic changes).
The low rates of systemic spread of the istope offer a definite advantage over previously used agents for radiation synovectomy, e.g. chemical such as osmic acid and alkylating agents, e.g (thiotepa and nitrogen mustard); several radionuclides in colloidal or particulate form, e.g. yttrium-90, gold-198, ebrium-169, rhenium-186, and phosphorus-32 (Sledge et al 1987). Dysphrosium-165 is a rare earth element with a half-life of 2.3 hours. It decays mainly by beta emissions. The maximum extent of penetration of the beta emission into the soft tissue is 5.7 millimetres, which probably approximates the entire synovial lining of the joint.