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Substance P releases histamine [ 57 ] leading to increased cutaneous capillary permeability without any fluid leakage through intact skin barrier. Substance P induces release of antigen-evoked mediators [ 58 ], tumor necrosis factor-alpha [ 59 ] and leukotrienes [ 60 ], which act as inflammatory mediators to enhance pain and tissue swelling. The interstitium plays a role in the development of edema in burns and in the induction of initial swelling in inflammation [ 61 ].

Based on that, pain conditions may benefit from cupping therapy through excretion of fluids containing the above-mentioned CPS Figure 2.

Pathogenesis of pain, headache and migraine. Possible role of treatment using wet cupping therapy. Goodwin gave the term inflammatory soup to the mixture of inflammatory cells as macrophages and lymphocytes together with chemical mediators e. Skin excretes many drugs, heavy metals, chemicals and endogenous toxic compounds. Skin has a drug metabolizing function [ 63 ], drug biotransformation function [ 64 ], antioxidant function [ 65 ] in addition to the excretory functions exerted by skin appendages e.

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Skin barrier retards excretion of accumulated toxins, while skin injury disturbs skin excretory functions [ 70 ] with retention of drugs and endogenous metabolites [ 71 - 73 ].

Based on that, cupping therapy is so beneficial as it opens skin barrier and enhances skin excretory role.

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Based on that, external suction pressure as that occurring in cupping therapy may enhance the excretion of tissue fluids filled with noxious substances.

When first vacuum pressure is applied during cupping therapy Figure 3A ; negative suction pressure collects interstitial fluids in the cupped area causing uplifting of the skin inside cups without any fluid leakage through skin skin barrier as intact skin prevents extrusion of tissue fluids Figure 3B to outside due to high content of dermal matrix substances dermatan sulfate, hyaluronic acid and chondroitin sulfatewhich constitute the ground substance surrounding the dermal fibrous components that contribute to the viscoelastic nature of the skin.

Dermis is strong and elastic due to its high content of elastin protein makes skin soft and elastic and helps skin sucking inside cups and collagen protein gives strength to skin [ 7677 ]. Collected fluids intervene between skin and subcutaneous tissues.

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This may help breaking connective tissue adhesions. Based on that, skin surface is very suitable for practicing cupping therapy for clearing tissue fluids and capillary fluids. Application of cups on skin. Skin uplifting starts to form due to viscoelastic nature of the skin and effect of negative pressure suctioning. Based on that, 1st cupping step in CPC method is very helpful in clearing capillary blood from excess fluids with wastes via filtration through capillary pores in the local cupped area as a preparatory step for further capillary blood clearance.

This may help breaking more connective tissue adhesions with a possible relief of tension muscular spasm. Based on that, all those constitute the scientific rationale of dry cupping therapy. Skin uplifting progressively increases in size due to viscoelastic nature of skin and effect of negative pressure suctioning.

Collected fluids inside skin upliftings contain collected interstitial fluids with causative pathological substances, filtered fluids from blood capillaries with causative pathological substances, hemolyzed blood cells hemolysed RBCs, WBCs and platelets and filtered soluble substances.

That fluid mixture does not contain intact blood cells as their sizes are much bigger than sizes of pores of skin capillaries and cannot be filtered. The fluid mixture is excreted in next steps. Partial clearance of interstitial spaces from causative pathological substances occurs. Partial clearance of capillary blood occurs through increased filtration at arterial end of capillaries and decreased absorption at venous end of capillaries leading to excretion of causative pathological substances.

Compression of the skin by the outline of sucking cups causes skin reactive hyperemia. This decreases progressively the absorption at the venous end of capillaries Figures 3C-3E.

Movement of filtered fluids towards skin upliftings away from capillaries adds a more decrease to absorption at the venous end of capillaries. Based on that, most of the tissue fluids containing CPS are not absorbed again to venous end of capillary circulation due to effect of cupping therapy. This may take substance P away from pain receptors and pain sensitive structures producing analgesic effect Figures 2 and 3. This may bathe nerve endings in collected fluids and reduce their stimulation [ 79 ].

This may decrease neurotransmission of pain sensation producing an analgesic effect. Analgesic effect of cupping therapy helps in decreasing pain sensation during subsequent superficial skin laceration step. Based on that, 1st cupping step in CPC method not in PC method has a strong analgesic effect, which allows doing subsequent skin puncturing with no need for analgesic or anesthetic administration. If skin upliftings are left for some time without skin puncturing dry cupping therapyfluid collections inside upliftings will leak and redistribute to underlying tissues causing disappearance of skin upliftings.

Improvement of pain instead of retention of inflammatory mediators and noxious substances may be due to dilution of those CPS and their redistribution to new sites away from pain receptors and pain sensitive structures after disappearance of skin upliftings.

In addition, skin puncturing allows release of endogenous opioids e. Derivatives of proopiomelanocortin e. Based on that, CPC method of wet cupping therapy is better than dry cupping therapy and PC method in treating pain as CPC method includes 2 advantages: Removal of sucking cups negative pressure causes a decrease in sucking pressure leading to a decrease in size of skin upliftings to the level of collected fluids. This increases capillary hydrostatic pressure leading to more capillary filtration and consequently more blood clearance.

The longer the duration of cupping for few minutesthe more accumulation of tissue fluid in the skin layers inside the cups around skin capillaries until an equilibrium point is reached at which no further fluid will accumulate. Escape and redistribution of fluids from skin uplift back to nearby tissues is prevented by maintained negative pressure during first cupping for few minutes.

Removal of negative pressure of cupping through removing cups prevents more accumulation of tissue fluid and instead, allows for slow fluid redistribution. Immediate skin pricking for few millimeters depth is recommended to prevent fluid redistribution and to get better cupping results.

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In this phenomenon, compression causes a reduction in blood flow to the skin for few minutes resulting in accumulation of metabolites and vasodilator chemicals. At the end of this step, vascular compression is removed causing a dramatic increase in blood flow to the skin known as reactive hyperemia, which may bring more blood to the skin circulation to be filtered and cleared during next steps of Al-hijamah CPC method.

C- 2nd step of wet cupping therapy skin puncturing In both CPC and PC method 1- Injury to skin as in puncturing step in cupping therapy causes a double phenomenon capillary reaction. In the first phenomenon, capillary permeability immediately increases for less than 10 minutes Figure 4. In the second phenomenon, a delayed increase in permeability begins Figure 4 about one hour after injury [ 8182 ]. Antihistamines affect the first phenomenon but not the second one [ 8182 ].

Increased capillary permeability in the first phenomenon is so helpful to enhance capillary filtration, blood clearance of intravascular fluids and fluid collection then movement of collected fluids towards skin puncture site to be excreted under effect of cupping therapy. Practically, this 10 minutes period is consumed in the second cupping step in the CPC method [ 7 ] and in creating skin upliftings then cupping step in the PC method [ 36 ].

Based on that, CPC method of wet cupping therapy makes better benefit of increased capillary permeability during this 10 minutes period and filters capillary blood during the whole period, while PC method consumes this time to create skin upliftings then collect fluids. CPC method may be more beneficial in blood clearance than PC method. Injuring skin causes opening of skin barrier and a traumatic injury to capillaries leading to bleeding in both cupping methods.

Tapping is needed only in the PC method to draw blood out. Based on that, in the CPC method, puncturing skin is less painful due to collection of fluids interstitial fluids and filtered fluids beneath the skin surface leading to decreased interstitial fluid pressure, which decreases pain sensation.

In addition, there is dilution and redistribution of the noxious agents, inflammatory mediators and CPS away from pain receptors and pain sensitive structures Figure 2while this is not the case in the PC method. In the PC method, pricking skin may be painful at the tender points beneath which pain-causing substances are existing.

In addition, localization of inflammation at certain sites produces local erythema and tenderness at these sites, which makes direct skin puncturing painful as in the PC method. Blood from injured capillaries becomes mixed with collected fluids interstitial fluids and filtered fluids beneath skin surface and starts to come out mixed with the collected fluids i.

In the PC method, fresh blood comes out rapidly as there is no prior collection of fluids to slow down its flow. Little tissue fluids are mixed with blood, as there is no filtered fluid from capillaries or collected interstitial fluids until this step in the PC method i.

The noxious substances that are present in the interstitial fluids are still present and not excreted in the PC method as noxious substances are not collected or diluted in fluids inside skin uplifting in the PC method.

In the CPC method, collected fluids enhance blood coagulation unlike the PC method, where fresh blood comes out under tapping effect. This leads to vasoconstriction, platelet plug formation to seal the bleeding siteformation of fibrin thrombus and activation of fibrinolytic system to prevent extension of the thrombus soon occurs.

Damaged endothelial cells releases tissue thromboplastin, which activates the extrinsic pathway of coagulation. Exposure of subendothelial collagen stimulates platelet adhesion and aggregation, activates factor XII intrinsic pathway of coagulation and activates fibrinolysis. Platelets soon aggregate to form a platelet plug.

In addition, platelets release ADP increases platelet release reactionsthromboxane A2 vasoconstrictorphospholipids platelet factor 3 that is essential for coagulation and platelet factor 4 that has a local anti-heparin effect and is essential for coagulation [ 84 ]. Based on that, it is essential to start 2nd cupping suction step immediately after skin skin puncturing in both CPC and PC methods.